CA2702922C - Spiro-condensed 1,3,4-thiadiazole derivatives for inhibiting ksp kinesin activity - Google Patents

Spiro-condensed 1,3,4-thiadiazole derivatives for inhibiting ksp kinesin activity Download PDF

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CA2702922C
CA2702922C CA2702922A CA2702922A CA2702922C CA 2702922 C CA2702922 C CA 2702922C CA 2702922 A CA2702922 A CA 2702922A CA 2702922 A CA2702922 A CA 2702922A CA 2702922 C CA2702922 C CA 2702922C
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nr23c
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nr25r26
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M. Arshad Siddiqui
Chaoyang Dai
Umar Faruk Mansoor
Liping Yang
Lalalnthi Dilrukshi Vitharana
Angie R. Angeles
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Merck Sharp and Dohme LLC
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Abstract

The present invention relates to compounds of Formula (I), below, (wherein X, R1, R2, R3, p, E, ring A, and ring B are as defined herein). The present invention also relates to compositions (including pharmaceutically acceptable compositions) comprising these compounds, alone and in combination with one or more additional therapeutic agents, and to methods for their use in inhibiting KSP kinesin activity, and for treating cellular proliferative diseases or disorders associated with KSP kinesin activity. Formula I [Chemical formula should be inserted here as it appears on abstract in paper form.]

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional volumes please contact the Canadian Patent Office.

SPIRO-CONDENSED 1,3,4 -THIADIAZOLE DERIVATIVES FOR INHIBITING KSP KINESIN
ACTIVITY
FIELD OF 'THE INVENTION
The present invention relates to compounds and compositions that are useful for treating cellular proliferative diseases or disorders associated with Kinesin Spindle Protein (KSP) kinesin activity and for inhibiting KSP kinesin activity.
BACKGROUND OF THE INVENTION
Cancer is a leading cause of death in the United States and throughout the world. Cancer cells are often characterized by consdtutive profiferative signals, defects in cell cycle checkpoints, as well as defects in apoptotic pathways.
There is a great need for the development of new chemotherapeutic drugs that can block cell proliferation and enhance apoptosis of tumor cells.
Conventional therapeutic agents used to treat cancer include taxanes and virica alkaloids, which target microtubules. Microtubuies are an integral structural element of the mitotic spindle, which is responsible for the distribution of the duplicated sister chromatids ba each of the daughter cells that result from cell division. Disiuption micnatubules or interference with microtubule dynamics can WM* cell division and induce aixiptosis.
However, microtubules are also important structural elements in non-proliferative cells. For example. they are required for organelle and vesicle transport within the ceN of along axons. Since miciotubule-targeted drugs do not discriminate between these different structures, they can have undesirable side effects that limit usefulness and dosage. There is a heed fof PtleatoffferaPelxic agents with improved specificity to avoid side effects and improve efficacy.
- 2 -Microtubules rely on two classes of motor proteins, the kinesins and dyneins, for their function. Kinesins are motor proteins that generate motion along microtubules. They are characterized by a conserved motor domain, which is approximately 320 amino acids in length. The motor domain binds and hydrolyses ATP as an energy source to drive directional movement of cellular cargo along microtubules and also contains the microtubule binding interface (Mandelkow and Mandelkow, Trends Cell Biol. 2002, 12:585-591).
Kinesins exhibit a high degree of functional diversity, and several kinesins are specifically required during mitosis and cell division. Different mitotic kinesins are involved in all aspects of mitosis, including the formation of a bipolar spindle, spindle dynamics, and chromosome movement. Thus, interference with the function of mitotic kinesins can disrupt normal mitosis and block cell division.
Specifically, the mitotic kinesin KSP (also termed EG5), which is required for centrosome separation, was shown to have an essential function during mitosis.
Cells in which KSP function is inhibited arrest in mitosis with unseparated centrosomes (Blangy et al., Cell 1995, 83:1159-1169). This leads to the formation of a nnonoastral array of microtubules, at the end of which the duplicated chromatids are attached in a rosette-like configuration. Further, this mitotic arrest leads to growth inhibition of tumor cells (Kaiser et aL, J.
BioL Chem.
1999, 274:18925-18931). Inhibitors of KSP would be desirable for the treatment of proliferative diseases, such as cancer.
Kinesin inhibitors are known, and several molecules have recently been described in the literature. For example, adociasulfate-2 inhibits the microtubule-stimulated ATPase activity of several kinesins, including CEINIP-E (Sakowicz et aL, Science 1998, 280:292-295). Rose Bengal lactone, another non-selective inhibitor, interferes with kinesin function by blocking the microtubule binding site (Hopkins et al., Biochemistry 2000, 39:2805-2814). Monastrol, a compound that has been isolated using a phenotypic screen, is a selective inhibitor of the KSP
motor domain (Mayer et al., Science 1999, 286:971-974). Treatment of cells with monastrol arrests cells in mitosis with monopolar spindles.
KSP inhibitors have been disclosed in patents or publications, including:
W02006/031348, W02006/110390, W02006/068933, W02006/023083,
- 3 -W02006/007491, W02006/086358, W02003/105855, W02006/023440, W02003/079973, W02004/087050, W02004/111193, W02004/112699, W02006/007497, W02006/101761, W02006/007496, W02005/017190, W00224/037171, W02005/019205, W02005/019206, W02005/102996, W02006/101780, W02006/007501, W02005/018547, W02004/058148, W02004/058700, W02005/018638, W02007/054138, W02006/133805, W02006/002726, W02006/133821, W02005/108355, W02006/094602, W02005/092011, W02006/031607, W02004/111023, W02006/137490, W02006/101102, W02006/101103, W02006/101104, W02006/101105, W02004/092147, W02005/035512, W02006/044825, W02006/044825, W02006/119146, US2006/0247178, W02006/098961, W02006/098962, US2006/0258699, US2007/0213380, U52007/0112044, US2007/0155804, US2008/0194653, W02008/042928, US2007/0249636, US2007/0287703, US2008/0153854, and US2007/0037853.
KSP, as well as other mitotic kinesins, are attractive targets for the discovery of novel chemotherapeutics with anti-proliferative activity. There is a need for compounds useful in the inhibition of KSP, and in the treatment of proliferative diseases, such as cancer.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a compound, or pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compound, said compound having the general structure shown in Formula (I):

R3)
- 4 -wherein X, R1, R2, R3, p, E, ring A, and ring B are selected independently of each other and wherein:
p is 0, 1, 2, 3, or 4;
X is selected from the group consisting of S, S(0), and S(0)2;
ring A (including E and the unsaturation shown) is a 4-3 membered cycloalkenyl or heterocycloalkenyl ring;
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0118)-, -N(C(Y)N(R6)(R13))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-., -N(R1,1)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-; -C-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-, wherein each Y is independently selected from the group consisting of (=0), (=S), (=N(R13)), (=N(CN)), (=N(OR14)), (=N(R15)(R16)), and (=C(R17)(R18));
ring B is an aromatic or heteroaromatic ring, or a partially unsaturated alicyclic = = ring, or a partially unsaturated heterocyclic ring, wherein said ring is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R13, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -SO2NR25R26, _c(0)R24, _c(0)0-20, _ SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR261:126, -NR23C(N-CN)NR26R26 and -NR23C(0)NR261:126;
R1 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl,
- 5 -wherein each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
R2 is selected from the group consisting of -C(Z)R7, -C(Z)NR2R16, -C(Z)01:18, -S02NR2R16, alkyl, heteroalkyl, aryl, heteroary1,-cycloal.kyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each Z is independently selected from the group consisting of (=0), (=S), (=N(R13)), (=N(CN)), (=N(0R14)), (=N(R15)(R16)), and (=C(R17)(R18)), and wherein each said alkyl, each said heteroalkyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said-cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo (with the proviso that said aryl and said heteroaryl are not substituted with oxo), halogen, -CN, -NO2>
alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R12, -0C(0)0R26, -NR21R22, -NR23902R24, -NR23c(0)0R20, -NR23C(0)R24, , -SO2NR25-26 11 0(0)1324, -0(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR251:126, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
- 6 -each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2, -0R19, -0C(0)0R20, -NR21R22, _NR23s021324, U(0)0R2 , -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(S)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26, -NR23C(0)NR25R26, and -NR23-C(NH)-N(R26)2, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R25, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0) R24, -C(0) NR25R26, H c.,(N-CN)NR25R26 and -NR23C(0)NR25R26, or, alternatively, when p is 2, 3, or 4, any two R3 groups bound to the same ring carbon atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, or a spiroheterocycloalkyl ring containing from one to three ring heteroatonns independently selected from the group consisting of -NH-, -NR6-, -S-, -S(0)-, -S(0)2-, and -0-, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(0)-, -S(0)2-, and -0-, or, alternatively, R2 and R3, together with the atom to which they are attached, are taken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring
- 7 -containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(0)-, -S(0)2-, and -0-, or a heterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(0)-, -S(0)2-, and -0-;
each R4 (when not joined with R5) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR--C(N-CN)NR25R26 and -NR23C(0)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, .
heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0C(0)0R29, -NR21R22, _NR23s02R24, _NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, _c (0) _ K C(0)0R20, -SR19, -S(0)R19, -S021119, -0C(0)R24, -C(0)NR25R26, _NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
each R5 (when not joined with R4) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR251196, -C(0)1194, -C(0)0R29, -SR19,
8 -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26;
wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR", -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR261326, -C(o)R24, _c( 0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26;
or, alternatively, R4 and R5, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R20, -NR21 2 R2, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -S02NR25R26, )11 C(0)0R20, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR261326 and -NR22C(0)NR26R26;
- 9 -each R6 is independently selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, -C(S)R24, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, = azido, -0R13, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR261:126, -C(0)R24, -C(S)R24, -C(0)0R26, -SR16, -S(0)R13, -S02R13, -0C(Or 24, rt C(0)NIR23-26, _ NIR¨C(N-CN)NR261:126 and -NR23C(0)NR261=126;
each R7 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NIR23C(0)R24, -SO2NR261:126, -C(0)R24, -C(0)0R26, -SR", -S(0)R13,
-10--S02R19, -0C(0)R24, -O(0)NR25R26, _ NR-2ac C(N-CN)NR25R29 and -NR23C(0)NR25R26;
each R9 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyc,.alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, _C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -502R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26;
= each R9 (when not joined with R19) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, _NR23s02R24, _N=-=23,=-=
l,(0)0R2 ,
- 11 --NR23C(0)R24, -SO2NR251326, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
each R19 (when not joined with R9) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo; halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, _ NR-SO2R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, _c(o)=-=24, _ C(0)0R2 , -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
or, alternatively, R9 and R19, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, _ NR-SO2R24, -NR23C(0)0R29, -NR23C(0)R24,
- 12 --S02NR25R26, C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)N11251126 and -NR23C(0)NR25R26;
each R" is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, - -heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, =
. =
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -SO2NR26R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR25R26;
each R12 is independently selected from the group consisting of H, alkyl, -=
heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R23, -NR21R22, -NR23S02R24, -NR23C(0)0R26,
- 13 --NR23C(0)R24, -SO2NR261126, -C(0)1324, -C(0)0R20, -SRI , -S(0)R19, -SO2R19, -OG(0)1124, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)N1326R26;
each R13 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkyrvyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21¨H22, NR23S021324, -NR23C(0)0R20, -NR23C(0)1124, -SO2NR261326, -C(0)R24, -C(0)0R20, -SRI , -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR261126, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26;
each R14 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,
- 14 -azido, -01116, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -S(0)R16, -S021:116, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
each R15 (when not joined with R16) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R12, -0C(0)0R26, -NR21F122, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR16, -S(0)R19, -SO2R16, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
each R16 (when not joined with R15) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl,
- 15 -heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
or, alternatively, R15 and R16, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR25R26, _N
11 U(N-CN)NR26R26 and -NR23C(0)NR25R26;
= each R17 (when not joined with R16) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -CN, -0C(0)0R26, -0R16, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR26R26, _c(0, _ )r-s-24 C(0)0R26, -SR", -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl,
- 16 -heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R18, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR28R28, -C(0)1:124, -C(0)0R20, -SR", -S(0)R18, -S02R18, -0C(0)R24, -C(0)NR281R28, -NR23C(N-CN)NR28R28 and -NR23C(0)NR281328;
each R18 (when not joined with R17) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -CN, -0C(0)0R2 , -0R18, -NR21R22, -NR23S02R24, -NR28C(0)0R20, -NR23C(0)R24, -SO2NR28R28, -C(0)R24, -C(0)0R20, -SR18, -S(0)R18, -SO2R18, -0C(0)R24, -C(0)NR28R28, -NR23C(N-CN)NR28R28 and -NR23C(0)NR28R28, wherein each said alkyl; each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently.selected.from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R18, -0C(0)0R28, -NR21R22, -NR23S02R24, -NR23C(0)0R20 , -NR23C(0)R24, -S02NR28R26, _c(0-24, _ C(0)0R2 , -SR18, -S(0)R18, -S02R18, -0C(0)R24, -C(0)NR28R28, -NR23C(N-CN)NR28R28 and -NR23C(0)NR28R28;
or, alternatively, R17 and R18, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S,
- 17 -wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR", -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and ¨NR23C(0)NR25R26;
each R19 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
each R2 is independently selected from the group consisting of H, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
each R21 (when not joined with R22) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
each 1,122 (when not joined with R21). is independently-selected 'from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
or, altematively, R21 and R22, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S;
each R23 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
each R24 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
- 18 -each R25 (when not joined with R26) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; and each R25 (when not joined with R25) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl;
or, alternatively, R25 and R26, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
As explained in more detail below, it shall be understood that ring A can have unsaturation in addition to the unsaturation shown in the generic formulas provided herein.
Pharmaceutical formulations or compositions comprising a therapeutically effective amount of at least one of the inventive compounds, and/or pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers thereof and a pharmaceutically acceptable carrier also are provided. Pharmaceutical formulations or compositions comprising a therapeutically effective amount of at least one of the inventive compounds (and/or pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers thereof) and a pharmaceutically acceptable carrier together with one or more additional active ingredients are also contemplated.
Methods of treating cellular proliferative diseases, disorders associated with KSP kinesin activity and/or for inhibiting KSP kinesin activity in a subject comprising administering to a subject in need of such treatment an effective amount of at least one of the inventive compounds or formulations or compositions according to the invention are also are provided. The methods according to the invention may be used in a single agent regimen or as part of a multiple agent regimen as is determined appropriate by those skilled in the art.
Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth
- 19 -used in the specification and claims are to be understood as being modified in all instances by the term "about."
DETAILED DESCRIPTION
In one embodiment, the compounds of the invention have a structure shown in Formula (I) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds.
As stated in Formula (I) (and in other formulas described herein depicting various embodiments of the compounds of the invention), ring A is a 4-8 membered cycloalkenyl or heterocycloalkenyl ring. It shall be understood that such cycloalkenyl or heterocycloalkenyl rings of ring A can have unsaturation that is in addition to the unsaturation shown in the generic formulas provided herein.
For purposes of illustration only, non-limiting examples of such additional unsaturation in ring A include:

)-1--x A
N

R2 R . Additional non-limiting examples include:
Ri )7_x 0 R, A nN ki N N
_3 I ,,3 R2 Fa ,and R2 R3 In one embodiment, in Formula (I), X is S.
In one embodiment, in Formula (I), X is S(0).
In one embodiment, in Formula (l), X is S(0)2.
In one embodiment, in Formula (l), ring A is a cycloalkenyl ring.
In one embodiment, in Formula (I), ring A is a heterocycloalkenyl ring.
- 20 -In one embodiment, in Formula (I), ring A is a 4-membered ring.
In one embodiment, in Formula (I), ring A is a 5-membered ring.
In one embodiment, in Formula (I), ring A is a 6-membered ring.
In one embodiment, in Formula (I), ring A is a 7-membered ring.
In one embodiment, in Formula (I), ring A is an 8-membered ring.
In one embodiment, in Formula (I), ring A (including the unsaturation shown) is mono-unsaturated.
In one embodiment, in Formula (I), ring A (including the unsaturation shown) is poly-unsaturated.
In one embodiment, in Formula (I), E is -C(R4)(R6)-.
In one embodiment, in Formula (I), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0118)-, -N(C(Y)N(R9)(R10))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(137)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, _cco_NoR11yN(R12)_, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In one embodiment, in Formula (I), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)1z124, -C(0)0R20, and -C(S)R24.
In one embodiment, in Formula (I), E is selected from the group consisting of -and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
- 21 -In one embodiment, in Formula (I), when E is -N(R6)-, then p is 0 and R3 is absent. In such embodiments, non-limiting examples of R6 include Ft, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, in Formula (I), E is -0, In one embodiment, in Formula (I), E is -S-.
In one embodiment, in Formula (I), E is -S(0)-.
In one embodiment, in Formula (I), E is -S(0)2-.
In one embodiment, in Formula (I), E is ¨CH2-=
In one embodiment, in Formula (I), E is ¨CHR4-.
In one embodiment, in Formula (I), E is ¨CR4R6-.
In one erhhodiment, in Formula (I), E is ¨N(R6)-.
In one embodiment, in Formula (I), E is -N(C(Y)R7)-.
In one embodiment, in Formula (I), E is -N(C(Y)0136)-.
In one embodiment, in Formula (I), E is -N(C(Y)N(133)(R16))-.
In one embodiment, in Formula (I), E is -C(0)-N(R11)-.
In one embodiment, in Formula (I), E is -N(R11)-C(0)-.
In one embodiment, in Formula (I), E is -S(0)2-N(R11)-.
In one embodiment, in Formula (I), E is -N(R11)-S(0)2-=
In one embodiment, in Formula (I), E is -C(0)-0-.
In one embodiment, in Formula (I), E is -0-C(0)-.
In one embodiment, in Formula (I), E is -0-N(R6)-.
In one embodiment, in Formula (I), E is -N(R6)-0-.
In one embodiment, in Formula (I), E is -N(R6)-N(R12)-.
=
- 22 -In one embodiment, in Formula (I), E is -N=N-.
In one embodiment, in Formula (I), E is -C(R7)=N-.
In one embodiment, in Formula (I), E is -C(0)-C(R7)=N-.
In one embodiment, in Formula (I), E is -C(0)-N=N-.
In one embodiment, in Formula (I), E is -0-C(Y)-N(R11)-.
In one embodiment, in Formula (I), E is -N(R11)-C(Y)-0-.
In one embodiment, in Formula (I), E is -N(R11)-C(Y)-N(R12)-.
In one embodiment, in Formula (I), E is -C(Y)-N(R11)-0-.
In one embodiment, in Formula (6, E Lt(Y)-N(R11)-N(R12)-.
In one embodiment, in Formula (I), E is -0-N(R11)-C(Y)-.
In one embodiment, in Formula (I), E is -N(R12)-N(1:111)-C(Y)-.
In one embodiment, in Formula (I), .Y is (=0).
In one embodiment, in Formula (I), Y is (=S).
In one embodiment, in Formula (I), Y is (=N(R13)).
In one embodiment, in Formula (I), Y is (=N(CN)).
In one embodiment, in Formula (0, Y is (=N(OR14)).
In one embodiment, in Formula (I), Y is (=N(R15)(R16)).
In one embodiment, in Formula (6, Y is (=C(R17)(R12)).
In one embodiment, in Formula (I), ring A is a 4-7-membered cycloalkylene ring and E is -C(R4)(R5)-.
- 23 -In one embodiment, in Formula (I), ring A is a 5-7-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0138)-, -N(C(Y)N(R9)(R10))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(117)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(0)2-, -N(R6)-, -C(0)-N(R11)-, and -N(R11)-C(0)-.
= =
In one embodiment, in Formula (I), ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-. In one such embodiment, in Formula (I), R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R20, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -0- and -N(R6)-. In one such embodiment, in Formula (I), R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R2 , and -C(S)R24. In one such embodiment, in Formula (I), ring A is a 5-membered heterocycloalkylene ring. In another such embodiment, in Formula (I), ring A is a 6-membered heterocycloalkylene ring.
In one embodiment, in Formula (I), ring A is a 4-membered ring and E is -C(R4)(R5)-.
- 24 -In one embodiment, in Formula (I), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0R8)-, -N(C(Y)N(R8)(R10))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In one embodiment, in Formula (I), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 4-membered ring and E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R20, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R8)-, -N(R6)-, -N(C(Y)137)-, -N(C(Y)0R8)-, -N(C(Y)N(R8)(R16))-.
In one embodiment, in Formula (I), A is a 4-membered ring and E is selected from the group consisting of -CH2-, -CH(R4)-, -C(R4)(R8)-.
In one embodiment, in Formula (I), ring A is a 5-membered ring and E is -C(R4)(R8)-.
In one embodiment, in Formula (I), ring A is a 5-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)R7)-, -S(0)2-N(R11)--, -N(C(Y)0R8)-, -N(C(Y)N(R8)(1:116))-, -C(0)-N(R1 _N(Ri 1 yc(0).,
- 25 --N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 5-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In one embodiment, in Formula (I), ring A is a 5-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 5-membered ring and E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R20, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 5-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)01:18)-, -N(C(Y)N(R9)(R10))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, and -C(R7)=N-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -0-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -S-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -S(0)-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -S(0)2-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -C(R4)(136)-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -N(R6)-.
In one embodiment, in Formula (I), A is a 5-mern6ered ring and E is -N(C(Y)R7)-.
- 26 -In one embodiment, in Formula (I), A is a 5-membered ring and E is -N(C(Y)0R8)-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -N(C(Y)N(R6)(R lo))..
In one embodiment, in Formula (I), A is a 5-membered ring and E is -C(0)-N(R11)-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -N(R11)-C(0)-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -S(0)2-N(R11)-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -N(R11)-S(0)2-.
In one embodiment, in Formula (l), A is a 5-membered ring and E is -C(0)-0-.
In one embodiment, in Formula (l), A is a 5-membered ring and E is -0-C(0)-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -0-N(R6)-.
In one embodiment, in Formula (l), A is a 5-membered ring and E.is -N(R6)-0-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -N(R6)-N(R12)-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -WA-.
In one embodiment, in Formula (I), A is a 5-membered ring and E is -C(R7)=N-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(R4)(R6)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)01:19)-, -N(C(Y)N(R9)(1119))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R")-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-,
- 27 --C(117)=N-, -C(0)-C(137)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R/1)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is selected from the= group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, in Formula (I), A is a 6-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0R8)-, -N(C(Y)N(R9)(R1 ))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -NI(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -0-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -S-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -S(0)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -S(0)2-=
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(R4)(R6)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(R6)-.
- 28 -In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(C(Y)137)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(C(Y)0R8)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(C(Y)N(138)(R10))-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(0)-N(R11)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(R11)-C(0)-.
In one embodiment, in Formula (I), ring A is a.6-membered ring and E is -S(0)2-N(R11)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(R11)-S(0)2-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(0)-In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -0-C(0)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -0-N(R6)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(R6)-0-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(R6)-N(R12)-.
= In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N=N-.
- 29 -In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(R7)=N-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(0)-C(R7)=N-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(0)-N=N-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -0-C(Y)-N(R11)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(R11)-C(Y)-0-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(R/1)-C(Y)-N(R12)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(Y)-N(R11)-0-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -C(Y)-N(R11)-N(R12)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -0-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 7-membered ring and E is -C(R4)(R6)-.
In one embodiment, in Formula (I), ring A is a 7-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0F18)-, -N(C(Y)N(R9)(R1 ))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-,
- 30 --N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-11(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 7-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In one embodiment, in Formula (I), ring A is a 7-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 7-membered ring and E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 7-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)F17)-, -N(C(Y)0R8)-, -N(C(Y)N(R9)(R10))-, -C(0)-N(R1 1 )-, -N(R1 1 )-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, =
-N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -0-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -S-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -S(0)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -S(0)2-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -C(R4)(R6)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R6)-.
- 31 -In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(C(Y)R7)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(C(Y)0R8)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(C(Y)N(R8)(R16))-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -C(0)-N(R1/)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R11)-C(0)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -S(0)2-N(R11)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R11)-S(0)2-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -C(0)-0-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -0-C(0)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -0-N(R6)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R6)-0-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R6)-N(R12)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N=N-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -C(R7)=N-.
In one embodiment, in Formula (l), A is a 7-membered ring and E is -C(0)-C(F17)=N-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -C(0)-N=N-.
- 32 -In one embodiment, in Formula (I), A is a 7-membered ring and E is -0-C(Y)-N(R11)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R11)-C(Y)-0-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R11)-C(Y)-N(R12)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -C(Y)-N(R11)-0-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -C(Y)-N(R11)-N(R12)-.
= = In one embodiment, in Formula (I), A is a 7-membered ring and E
is -0-.
N(R11)-C(Y)-.
In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R12)-N(R11)-C(Y)-.
=
In one embodiment, in Formula (I), ring A is a 8-membered ring and E is -C(R4)(R6)-.
In one embodiment, in Formula (I), ring A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0F18)-, -N(C(Y)N(R9)(R16))-, -C(0)-N(R//)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(117)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), ring A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
- 33 -In one embodiment, in Formula (I), ring A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R20, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 8-membered ring and E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, in Formula (I), ring A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0R8)-, -N(C(Y)N(R6)(R16))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(.R' 1)--S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-; -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -0-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -S-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -S(0)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -S(0)2-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -C(R4)(R6)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(R6)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(C(Y)R7)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(C(Y)0R8)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(C(Y)N(R9)(R16))-.
- 34 -In one embodiment, in Formula (l), A is a 8-membered ring and E is -C(0)-N(R11)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(R11)-C(0)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -S(0)2-N(R11)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is In one embodiment, in Formula (I), A is a 8-membered ring and E is -C(0)-0-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -0-C(0)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -0-N(R6)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(R8)-0-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is _N(R6)..N(R12)_.
In one embodiment, in Formula (I), A is a-8-membered ring and E is -N=N-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -C(R7)=N-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -C(0)-C(R7)=N-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -C(0)-N=N-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -0-C(Y)-N(R11)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(R11)-C(Y)-0-.
- 35 -In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(R11)-C(Y)-N(R12)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -C(Y)-N(R11)-0-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is 1)_N(R12)_.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -0-N(R11)-C(Y)-.
In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(R12)-N(R11)-C(Y)-.
=
In one embodiment, in Formula (I), ring B is an unsubstituted or substituted benzo or an unsubstituted or substituted thiophenyl ring.
In one embodiment, in Formula (I), ring B is an unsubstituted benzo or an unsubstituted thiophenyl ring.
In one embodiment, in Formula (I), ring B is an unsubstituted aromatic ring or an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroalyl-alkyl-, cycloalkyt, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, _NR23s02R24, _N-23¨
H L;(0)OR29, -NR23C(0)R24, -S02NR25R26, C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25.-.26, NR¨ 9q C(N-CN)NR25R26 and ¨NR23C(0)NR25R26.
In one embodiment, in Formula (I), ring B is an unsubstituted benzo ring or a benzo ring which is substituted with one or more substituents, which can be the
- 36 -same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroallwl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -Nee, -NR23S021124, -NR23C(0)0R20t _NR23c(0)R24, -S02NR26R26, -C(0)R24, _ C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and ¨NR23C(0)NR26R26.
In one embodiment, in Formula (I), ring B is an unsubstituted or substituted heteroaromatic ring or a substituted heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloaikyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NI:2 C(0)0e, -NR23C(0)1324, -S02N11261:126, -C(0)R24, -C(0)01329, -SR19, -S(0)R19, -502R19, -0C(0)R24, -C(0)NR26R26, -N1323C(N-CN)NR26R26 and ¨
NR23C(0)NR26R26. In one such embodiment, in Formula (I), ring B is a 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be =
the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2.
In one embodiment, in Formula (I), ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, - . thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
In one embodiment, in Formula (I), ring B is an unsubstituted aromatic ring.
- 37 -In one embodiment, in Formula (I), ring B is an unsubstituted benzo ring, and Formula (I) has the general structure:
1:11.rx =
R3 )N A

In one embodiment, in Formula (l), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0C(0)0R26, -NR21¨R 22, _ NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and ¨
NR213C(0)NR26R26.
In one embodiment, in Formula (I), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, NR23S02R24, -NR25C(0)0R20, -NR23c(o)R24, -s02NR25R26, c(o)0R2 , -sR19, -s(o)R19, -s02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR261126 and ¨
NR23C(0)NR261126.
- 38 -In one embodiment, in Formula (I), B is an unsubstituted heteroaromatic ring.
In one embodiment, in Formula (I), B is an unsubstituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2.
In one embodiment, in Formula (I), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, INR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR26R26, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), B is a 5-6-membered heteroaromatic ring = having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R13, -0C(0)01326, -NR2,R22, -NR23s02R24, -NR23C(0)0R20, _NR23c(0.-)1124, _ SO2NR25R26, _c(c)-.24, _ C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, _N =-.23=-=
u(N-CN)NR25R26 and -NR23C(0)NR25R26.
- 39 -In one embodiment, in Formula (I), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In one embodiment, in Formula (I), B is a 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, "*Ioalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, _NR23s02R24, L.,(0)0R20, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R213, -SR13, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR26R26.
In one embodiment, in Formula (I), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and O.
In one embodiment, in Formula (I), B is a 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR26R26, -C(0)R24, -C(0)0R26, -SR16,
- 40 --S(0)R19, -S02R19, -0C(0) R24, -C(0)N R25 _ NR¨C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), B is an unsubstituted 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In one embodiment, in Formula (I), B is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, _NR23s02R24, u(0)0R26, -NR23C(0)R24, -S02NR251326, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R19, -0C(0)R24, -C(0)NR25R26, NR¨C(N-CN)NR251126 and -NR23C(0)NR251126.
In one embodiment, in Formula (I), B is an unsubstituted 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and O.
In one embodiment, in Formula (I), B is a 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0 R2 , -NR21R22,
- 41 --NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2N R25-R, _ 26 C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), B is a 5-membered heteroaromatic ring having S as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroa141, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, 9:4 heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, _ NR¨SO2R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR25R26, -C _c(0)0R20, -S(0)R19, -S02R16, -0C (0)R24, -C (0)N R2611.-.26, _ R23C (NI -CN)N R26 =
R26 and =
-NR23C(0)NR25R26.
In one embodiment, in Formula (I), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom.
In one embodiment, in Formula (I), B is a thiophenyl group.
In one embodiment, in Formula (I), B is selected from the group consisting of rfssyand In one embodiment, in Formula (I), B is a pyridine.
In one embodiment, in Formula (I), B is a partially unsaturated alicyclic ring, which ring is unsubstituted.
In one embodiment, in Formula (I), B is a partially unsaturated alicyclic ring which is substituted with one or more substituents, which can be the same or different,
- 42 -each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloarkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR251:126, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), B is a partially unsaturated heterocyclic ring, which ring is unsubstituted.
In one embodiment, in Formula (I), B is a partially unsaturated heterocyclic ring which is substituted with one or more substituents, which can be the same or == different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), R1 is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21 -22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR251:126.
In one embodiment, in Formula (I), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being
- 43 -independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloalkyl.
In one embodiment, in Formula (I), R1 is unsubstituted aryl.
In one embodiment, in Formula (I), RI is unsubstituted phenyl.
In one embodiment, in Formula (I), R1 is unsubstituted naphthyl.
In one embodiment, in Formula (I), R1 is substituted aryl.
In one embodiment, in Formula (I), R1 is substituted phenyl.
In one embodiment, in Formula (I), RI is substituted naphthyl.
In one embodiment, in Formula (I), RI is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selectedirom the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R13, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -S02NR25R26, _c(c)-.24, O(0)0R26, -SR19, -S(0)R19, -_SO2R19, 70O(0)R24, -C(0)NR25R26, -NR23O(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), R1 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -01313, -0C(0)0R26, -NR2IR22, -NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -s02NR25R26, _coy O(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -O(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
- 44 -In one embodiment, in Formula (I), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloalkyl.
In one embodiment, in Formula (I), R1 is selected from the group consisting of:
halo/¨ HO /\ NC,../.... 02N/,..¨
`,.,..
NS ./ __ halo / __ halo S / __ halo (\ haJJ
allcyl,,...../¨ haloalkyl.õ/õ.¨

S. / _____________ halo ,and ,r. j ______________________________ halo . . ¨
=
sxj4.
In one embodiment, in Formula (I), R1 is:
perfluoroalkyl.,........,/¨
______________________ halo 1 0 . - -In one embodiment, in Formula (I), R1 is phenyl substituted with one to three fluoro groups.
In one embodiment, in Formula (I), R1 is phenyl substituted with two fluoro groups.
In one embodiment, in Formula (I), R1 is phenyl substituted with one fluoro group.
In one embodiment, in Formula (I), R1 is:
. F
_
- 45 -In one embodiment, in Formula (I), R2 is selected from the group consisting of -C(0)1R7, -C(0)NR8R16, and -C(0)0R8.
In one embodiment, in Formula (I), R2 is -C(Z)R7.
In one embodiment, in Formula (I), R2 is -C(Z)NR2R16.
In one embodiment, in Formula (I), R2 is -C(Z)0R8.
In one embodiment, in Formula (l), R2 is -S02NR8R16.
In one embodiment, in Formula (I), R2 is alkyl.
In one embodiment, in Formula (I), R2 is heteroallvl.
In one embodiment, in Formula (I), R2 is aryl.
=
In one embodiment, in Formula (I), R2 is heteroaryl.
In one embodiment, in Formula (I), R2 is cycloalkyl.
In one embodiment, in Formula (I), R2 is cycloalkenyl.
In one embodiment, in Formula (I), R2 is heterocycloalkyl.
In one embodiment, in Formula (I), R2 is heterocycloalkenyl.
In one embodiment, in Formula (I), Z is (=0).
In one embodiment, in Formula (I), Z is (=S).
In one embodiment, in Formula (I), Z is (=N(R13)).
In one embodiment, in Formula (I), Z is (=N(CN)).
In one embodiment, in Formula (I), Z is (=N(0R14)).
In one embodiment, in Formula (I), Z is (=N(R15)(R16)).
In one embodiment, in Formula (I), Z is (=C(R17)(R18)).
In one embodiment, in Formula (I), R2 is -C(Z)R7, and Z is (=0).
- 46 -In one embodiment, in Formula (I), R2 is ¨C(0)H.
In one embodiment, in Formula (I), R2 is ¨C(0)alkyl.
In one embodiment, in Formula (I), R2 is ¨C(0)CH3.
In one embodiment, in Formula (I), R2 is ¨C(0)117, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, _NR21 NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -502NR26R26, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR26.-.26, NR¨ 23 C(N-CN)NR29R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -0R19, -NR2/ R22, and cycloalkyl.
In one embodiment, in Formula (I), R2 is ¨C(0)137, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.
In one embodiment, in Formula (I), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH2, and cyclopropyl.
In one embodiment, in Formula (I), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each
- 47 -substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In one embodiment, in Formula (I), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with -OH.
In one embodiment, in Formula (I), R2 is ¨C(0)R7, wherein said R7 is unsubstituted heterocycloalkyl.
In one embodiment, in Formula (I), R2 is¨C(0)R7, wherein said R7 is substituted heterocycloalkyl.
In one embodiment, in Formula (I), R2 is ¨C(0)R7, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cYcloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R S021:113, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), R2 is ¨C(0)R7, wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted nnorpholine, substituted pyrrolidine, and substituted azetidine.
In one embodiment, in Formula (I), R2 is a moiety selected from the group consisting of:
- 48 ¨c¨

¨c¨

II
¨c¨

, , , HN
11_ alkyl/N _c_ I _ II
, and HN
In one embodiment, in Formula (I), R2 is -C(0)NR9R19.
In one embodiment, in Formula (I), R2 is ¨C(0)NF12.
In one embodiment, in Formula (l), R2 is ¨C(0)NR9R19, wherein R9 and R19 can be the same or different, each being independently selected from alkyl.
In one embodiment, in Formula (I), R2 is ¨C(0)NR9R19, wherein R9 is unsubstituted heterocycloalkyl and R19 is selected from the group consisting of H
and alkyl.
In one embodiment, in Formula (I), R2 is ¨C(0)NR9R19, wherein R9 is substituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl.
In one embodiment, in Formula (I), R2 is ¨C(0)NR9R19, wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R19 is selected from the group consisting of H and alkyl.
In one embodiment, in Formula (I), R2 is selected from the group consisting of:
alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)R7. ¨C(0)0R9, and -C(0)NR9R19.
Non-limiting examples of R2 include the following moieties:
- 49 -CF 3, o ctiFz, F.,,,L0, .2' , 04)'"s A , .r-r jjrc , *' 0 0 T 0 0 0 v-11--v, vi0H -1,---t, , OA_ ..),...,40 Nyõko .(, 11, A , O's. , OH , OH
..,.., ,Pr 0 po coNissts o 1 ¨ ojIl NH2 NH2 , O, ,NH, , . .
.r, -rrr' 0C) '=
, .) OJNI 0.,,' .jr=i' 0 0j1r 0 0\ fiNõ,_0 HNN ,-.14H
NH2 1 i- &
H2N , H2N , , . e= 0" 0 crktl .Gto '-el H2N
' .prt ,r-rr 0 ,,,,,.- 0 , cc,õ
O
0 ctiti ctiii olr. c-(S)NH ,cf() , H2N H2N , .rr sr%
cicdO .=40 ,,,,' cd"6 ""'" ,,,,, o I cN, ',,,D
.2 , N , N , \ --NH ,O-" , ,nn 0 0'411 0 > 0 / \
OiN'N1:) 1YNC \
0 0 ,...
NA N -- N¨

H
H , and 1 __ l .
- 50 -o In one embodiment, in Formula (I), R2 is 71/44 r3 In one embodiment, in Formula (I), Fr is .

In one embodiment, in Formula (I), R-= is .

In one embodiment, in Formula (I), R2 is `t, In one embodiment, in Formula (I), R2 is µ4 =o In one embodiment, in Formula (I), R-2 NH2 is 4 }-=
1=4 N
In one embodiment, in Formula (I), R2 is =
0 =
N _______________________________________ (TN¨

In one embodiment, in Formula (I), R2 is .
In one embodiment, in Formula (I), p is 0 and R3 is not present.
In one embodiment, in Formula (I), p is 1.
In one embodiment, in Formula (I), p is 2.
In one embodiment, in Formula (I), p is 3.
In one embodiment, in Formula (I), p is 4.
In one embodiment, in Formula (I), p is 2, 3, or 4, and at least two groups 1:13 are attached to the same ring atom.
-51 -In one embodiment, in Formula (I), p is 1, 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R20, -NR21R22, _c(0)R2.4, -C(S)R24, _ C(0)0R2 , and -C(0)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0F120, -NR211R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR25R26, -C(0)1:324, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR2519.26, =
-NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), p is 1 and R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)01120, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NIR23C(0)NR251:126.
In one embodiment, in Formula (I), p is 2, 3, or 4 and at least two groups 113 are bound to the same ring carbon atom, wherein each R3, which may be the same or different, is independently selected from the group consisting of alkyl,
- 52 -heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR261126, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NIR26R26, K u(N-CN)NR25R26 and -NR23C(0)NR26R26.
In one embodiment, in Formula (I), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein two R3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
In one embodiment, in Formula (I), each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R20, _N R21 R22, _N R23s02 R24, K U(0)0 R2 , -NR23C(0)R24, -S02N R25R26, -C(0)R24, _ C(S)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0) R24, -C(0)NR291:126, -NR23C(N-CN)N R2511 _NR23C(0)NR26R26, and -NR23-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R23, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR26R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26.
In one embodiment, in Formula (I), each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl,
- 53 --CN, -NO2, -0R19, -0C(0)0R26, -NR21.-s22, C(0)R24, -C(S)F124, -C(0)0R26, and -C(0)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0) _S02NR25R26, _c(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25-26, _ C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (I), p is 2, 3, or 4, and any two R3 groups bound to the same ring A atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, a spiroheterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(0)-, -S(0)2-, and -0-, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-,
- 54 --NR6-, -S-, -S(0)-, -S(0)2-, and ¨0-. Non-limiting examples of compounds of the invention in which two R3 groups are thus taken together include:

0 * F AL
N-NF S Wo ON= N'N
and NH.
In one embodiment, in Formula (I), R2 and R3 aretaken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of ¨NH-, -NR6-, -S-, -S(0)-, -S(0)2-, and ¨0-, or a hetercioycloalkenyl ring containing from one to three ring heteroatonns independently selected from the group consisting of ¨NH-, -NR6-, -S-, -S(0)-, -S(0)2-, and ¨0-. Non-limiting exarnples of a compound of the invention in which R2 and R3 are thus taken together include the following compound:
= * NH
"
F N--In one embodiment, in Formula (I), R3 is alkyl.
In one embodiment, in Formula (I), R3 is heteroalkyl.
In one embodiment, in Formula (I), R3 is alkenyl.
In one ernbodiment, in Formula (I), R3 is heteroalkenyl.
In one embodiment, in Formula (I), R3 is alkynyl.
In one ernbodiment, in Formula (I), R3 is heteroalkynyl.
In one embodiment, in Formula (I), R3 is aryl.
In one embodiment, in Formula (I), R3 is heteroaryl.
- 55 -In one embodiment, in Formula (I), R3 is cycloalkyl.
In one embodiment, in Formula (I), R3 is cycloalkenyl.
In one embodiment, in Formula (I), R3 is heterocycloalkyl.
In one embodiment, in Formula (I), FI3 is heterocycloalkenyl.
In one embodiment, in Formula (I), R3 is halogen.
In one embodiment, in Formula (I), R3 is ¨CN.
In one embodiment, in Formula (I), R3 is -NO2.
In one embodiment, in Formula (I), R3 is -0R19.
In one embodiment, in Formula (I), R3 is -0C(0)0R29.
In one embodiment, in Formula (I), R3 is _NR211422,.
In one embodiment, in Formula (I), 1:13 is -NR23S02R24.
In one embodiment, in Formula (I), R3 is -NR23C(0)0R29.
In one embodiment, in Formula (I), R3 is -NR23C(0)R24.
In one embodiment, in Formula (I), R3 is -S02NR29R26.
In one embodiment, in Formula (I), 113 is -C(0)R24.
In one embodiment, in Formula (I), R3 is -C(S)R24.
In one embodiment, in Formula (I), R3 is -C(0)0R29.
In one embodiment, in Formula (I), R3 is -SR19.
In one embodiment, in Formula (I), R3 is -S(0)R19.
In one embodiment, in Formula (I), R3 is -SO2R19.
In one embodiment, in Formula (I), R3 is -0C(0)R24.
In one embodiment, in Formula (I), R3 is -C(0)NR29R26.
In one embodiment, in Formula (I), R3 is -NR23C(N-CN)NR25R26.
In one embodiment, in Formula (I), R3 is ¨N R23C(0)NR25R26.
- 56 -Non-limiting examples of R3 include the following: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl, .risrr ..""nx= '11.1... , ILI LI **) NH2, H2N , H2N , OH, OH, HO, 1....i -JVVV, .rtrunr H L-1 Li¨OH =Lr--NH2 HN
HN)i---NH2 ,t0H
= . . .
. ' )-- HN
, \ , 0 , N\ ,'OH , and H2 N .
In one embodiment, in Formula (I), when E is ¨NR6-, R3 is absent.
In one embodiment, Formula (I) has the general structure shown in Formula (I.a):

e R3) N P
N
I

(I.a).
In one embodiment, Formula (l) has the general structure shown in Formula (I.b):

X 411) R 3 ) - A
-N

(I.b).
In one embodiment, Formula (I) has the general structure shown in Formula (I.c):

X al N A R 3 )P
I

(I.c), wherein p is 0, 1, 2, or 3.
In one embodiment, Formula (I) has the general structure shown in Formula (I.d):
R 110) 1 R 3 ) N A

(I.d), wherein p is 0, 1, 2, or 3.
In one embodiment, Formula (I) has the general structure shown in Formula (I.e):

)7_-x N A R3) (I.e), wherein p is 0, 1, 2, or 3.
In one embodiment, Formula (I) has the general structure shown in Formula (I.f):

X 41) (R3 )N A
I =-2 ¨

(1.0, wherein p is 0, 1, 2, or 3.
In one embodiment, Formula (I) has the general structure shown in Formula (I.g):

R )13 (I.g), wherein p is 0, 1, 2, or 3.
In some embodiments, in each of formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), and * F
(I.g), R1 is / and the compounds of the invention have the general structure shown in Formula (I.h):
44, F
, x R3) N A

(I.h), wherein p is 0, 1, 2, or 3.
In some embodiments, in each of Formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g), and (I.h), p is O.

For the various embodiments of the present invention described herein, it shall be understood that any variable of a structural formula not explicitly defined therein is as defined in the formula to which the embodiment refers. It shall also be understood that each R3, when present, is attached to a ring atom or ring heteroatom of ring A by replacement of an available hydrogen atom.
In other embodiments, in each of Formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g), and (I.h):
ring A is a 4-7 membered cycloalkenyl ring;
E is ¨C(R4)(R6)-; and ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted =
with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, . -0C(0)0R20, -NR21R22, _NR23s02R24, 11 L. (0)0 R213, -NR23C(0)R24, -S02NR29R26, ) C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR261R26 and ¨NR23C(0)NR26R26.
In other embodiments, in each of Formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), and (I.g):
ring A is a 4-7 membered cycloalkenyl ring;
E is ¨C(R4)(F16)-; and ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR261126, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR261326, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-NO2, -NR21R22, and haloalkyl;
R2 is selected from the group consisting of: alkyl,.haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)1R7. -C(0)01=18, and -C(0)NIR9R1 ; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R2 , -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(S)R24, -C(0)0R213, -S(0)R19, -S021=1/9, -0C(0)R24, -C(0)NR26F126, -NR23C(N-CN)NR26R26, -NR23C(0)NR25R26, ad -NR23-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -S02NR29R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S021:09, -0C(0)R24, -C(0)NR291126, -NR23C(N-CN)NR26R26 and -NR23C(0)NR25R26.

In other embodiments, in each of Formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), and (I.g):
ring A is a 4-7 membered cycloalkenyl ring;
E is ¨C(R4)(R5)-;
ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, 420R19, -.--0C(0)0R2 , -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR25R26, _cp) =-= 1124, C(0)0 R2 , -S R19, -S(0)Rig, -S02R19, -0C(0)R24, -C(0) NR25R26, -NR23C(N-CN)NR25R25 and ¨NR23C(0)NR25R26;
141 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloalkyl;
R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)R7. ¨C(0)0R9, and -C(0)NR9R10; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R20, -NR21R22, _c(0)R24, _c(s..-=)11; _24 C(0)0R2 , and -C(0)NR251:126, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR15, -S(0)R16, -S02R15, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In other embodiments, in each of Formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), and (I.g):
ring A is a 4-7 membered cycloalkenyl ring;
E is ¨C(R4)(R5)-; and ring B is a benzo ring or a 5-6 mernbered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkryl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -ocm0l=12 , -N R21 1-.22, NR-2:1 SO2R24, -NR23C(0)0R26, -NR25C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R15, -S02R16, -0C(0)R24, -C(0)NeR26, -NR23C(N-CN)NR25R26 and ¨NR23C(0)NR25R26;
R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,- _NR21R22 - , NO2, and haloalkyl;
R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)F17. ¨C(0)0116, and -C(0)N1131116; and p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -01116, -0C(0)0R26, -NR21R22, -NR23S02R24, -NIR23C(0)0R26, -NR23C(0)R24, -S02NR261126, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR261326, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26.
In other embodiments, in each of Formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g), and (I.h):
ring A is a 5-6 membered heterocycloalkenyl ring;
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)137)-, -N(C(Y)0146)-, -N(C(Y)N(R6)(R16))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -N(1=111)-C(Y)-, and -N(R12)-N(R11)-C(Y)-; and ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR261:126, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR261126.

In other embodiments, in each of Formulas (I), (I.a), (I.b), (Lc), (I.d), (I.e), (I.f), and (I.g):
ring A is a 5-6 membered heterocycloalkenyl ring;
E is selected from the group consisting -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24;
ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of = halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, = alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0O(0)0R20, _NR21 R22, _NR23s02R24, _NR23c(0)0R20, _NR23c (o)R24, -S02NR261326, -C(0)R24, -C(0)0R26, -SR16, -S(0)R13, -S02R16, -0C(0)1324, -C(0)NR26R26, 1-1 u(N-CN)NR261126 and -NR23C(0)NR26R26;
= R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-NO2, -NR21R22, and haloalkyl;
R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)F17. -C(0)01=18, and -C(0)NR31:116; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R13, -0C(0)0R26, -NR211,122, -NR23so2R24, -NR23C(0)0R26, -N R23c(cy )11 _ SO2NR25R26, _c(o)R24, -C(S)F124, -C(0)0R26, -SR13, -S(0)R13, -S02R16, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR261326, -NR23C(0)NR26R26, and -NR23-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkpyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, -NR23s02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR261126, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR261426, -NR23C(N-CN)NR261326 and -NR23C(0)NR26R26.
In other embodiments, in each of Formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), and (I.g):
ring A is a 5-6 membered heterocycloalkenyl ring;
E is selected from the group consisting -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24;
ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted = with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR", -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR26R26, -C(0)R24, -C(0)0R20, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR261126 and -NR23C(0)NR261126;
R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -C1\1,-NO2, -NR21 R22, and haloalkyl;
R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)117. --C(0)0R8, and -C(0)NR9R113; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R29, -N R21 R22 , -C(0) R24, _c(s, )11 C(0)0R20, and -C(0)NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25F126, -NR23C(N-CN)NR25R26 and -NR23C(0)NR251196.. -.-In other embodiments, in each of Formulas (I), (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), and (I.g):
ring A is a 5-6 membered heterocycloalkenyl ring;
E is selected from the group consisting -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R29, and -C(S)R24;
ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -N R21 .+22, _ NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and ¨NR23C(0)NR25R2s;
R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -NR21R22, and haloalkyl;
R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)117. ¨C(0)0119, and -C(0)NR9R16; and p is 1 and 1:13 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or ' = -different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, = -C(0)0R29, -SR19, -S(0)R19, -502R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR26F126 and -N R23C(0)N R25R26. "
In one embodiment, the compounds of the invention have a structure shown in Formula (II) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:

X

(11) wherein X, R1, R2, E, and ring B are selected independently of each other and wherein E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R5)-, -N(115)-, -N(C(Y)R7)-, -N(C(Y)0115)-, -N(C(Y)N(R9)(R10)).;
and ring B, X, 131, R2, R4, R5, R6, R7, R5, R9, Rro, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I).
In one embodiment, in Formula (II):
= =
E is selected from the group consisting of ¨0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R5)-, and -N(R6)-;
ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and friazinyl;
R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloalkyl; and R2 is selected from the group consisting of -C(0)R7, -C(0)NR9R10, and -C(0)0R8.

In one embodiment, in Formula (II):
R1 is:
F
In one embodiment, the compounds of the invention have a structure shown in Formula (II.a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:

X
N

(l1.a.) wherein X, R1, R2, E, and ring B are selected independently of each other and wherein:
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)F17)-, -N(C(Y)0138)-, -N(C(Y)N(1:16)(Fl10))-.
ring B is a substituted or unsubstituted aromatic ring;
and X, R1, R2, R4, R5, R6, R7, R5, Rs, R1(:), Y and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I).
In one embodiment, Formula (II.a.) has the general structure shown in Formula (II.a.1):

N

(II.a.1).
In one embodiment, Formula (II.a.) has the general structure shown in Formula (II.a.2):
. = = R1 X
N

(11 .a.2).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), X is S.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), X is S(0).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), X is S(0)2.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -C(R4)(R5)-.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R9 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -0-.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -S-.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -S(0)-.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (11.a.2), E is -S(0)2-.
In some embodiments, in each of Formulas (II.a.), (11.a.1), and (II.a.2), E is -C(R4)(R9)-.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -N(R6)-.
In some embodiments, in each of Forrnulas (II.a.), (II.a.1), and (11.a.2), E
is -N(C(Y)R7)-.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -N(C(Y)0F19)-.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), E is -N(C(Y)N(R9)(R10)), In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Y is (=0).
In some embodiments, in each of Formulas (11.a.), (II.a.1), and (II.a.2), Y is (=S).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (11.a.2), Y is (=N(R13)).

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Y is (=N(CN)).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Y is (=N(0R14)).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Y is (=N(R15)(R.16)).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Y is (=C(R17)(R18)).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), B is an unsubstituted aromatic ring.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (l1.a..2), B
is an unsubstituted benzo ring, and Formula (II.a.) has the general structure:

X

N
=
N=

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), B is an unsubstituted benzo ring, and Formula (II.a.) has the general structure:

N

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R13, -0C(0)0R23, K NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -SO2NR261126, -C(0)R24, -C(0)0R23, -SR13, -S(0)R13, -S02R13, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR25R26 and ¨NR23C(0)NR25R26.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, 2f4 NR¨SO2R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR261:126, -C(0)R24, -C(0)0R26, -5R16, -S(0)R13, -S021113, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and ¨NR23C(0)NR261:126.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R' is unsubstituted aryl.

In some embodiments, in each of Formulas (Il.a.), (II.a.1), and (II.a.2), R1 is unsubstituted phenyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is unsubstituted naphthyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is substituted aryl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is substituted phenyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is substituted naphthyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, U(0)0 R2 -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR26R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR261:126.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO2, -NR21R22, and haloalkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), 131 is selected from the group consisting of:
halo /¨

\.. FO/¨
' /
`.... NC,.../.....¨ 02N,..../....
4\\ /...0 _______________ halo S halo k% / \ ___ halo ..rfjj sJJ SJJ'S , , , , alky4.....4.¨ haloalkyl,".....¨

, and .
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is:
perfluoroalkyl,,,, ../¨
ks / ____________________ halo , .
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is phenyl substituted with one to three fluoro groups.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), 111 is phenyl substituted with two fluoro groups.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), 131 is phenyl substituted with one fluoro group.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R1 is:

.EPrj In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -C(Z)F17.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -C(Z)NR8R10.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -C(Z)0R8.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -502NR81=00.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is alkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is heteroalkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is aryl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is heteroaryl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is cycloalkyl.
.1n some.embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2). R2 is cycloalkenyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is heterocycloalkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is heterocycloalkenyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Z is (=0).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Z is (=S).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (11.a.2), Z is (=N(R13)).

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Z is (=N(CN)).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Z is (=N(0R14)).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Z is (=N(R15)(R16)).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), Z is (=C(R17)(R19)).
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -C(Z)R7, and Z is (=0).
In some embodiments, in each of Formulas.(11.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)H.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)alkyl.
In some embodiments, in each of Formulas (11.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)C/13.
In some embodiments, in each of Formulas (11.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)117, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R13, -0C(0)0R2 , -NR21R22, -NR23S02R24, -NR23C(0)0R20, _NR23c(cr.-.24, _ )rt S02NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR29R26, -NR23C(N-CN)NR29R26 and -NR23C(0)NR29R26.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)F17, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -0R19, -NR21R22, and cycloalkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)R7, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH2, and cyclopropyl.
=
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)147, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (11.a.2), R2 is ¨
C(0)R7, wherein said R7 is alkyl substituted with -OH.
In some ernbodiments, in each of Formulas (II.a.), (11.a.1), and (II.a.2), R2 is ¨
C(0)117, wherein said R7 is unsubstituted heterocycloalkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)R7, wherein said R7 is substituted heterocycloalkyl.
In some embodiments, in each of Formulas (11.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)R7, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)01129, -NR211122, -NR23S021124, -N1323C(0)0R29, -N1123C(0)R24, -S02NR29R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR29R26, -NR23C(N-CN)NR29R26 and -NR23C(0)NR29R26.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -C(0)117, wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is selected from:
t:11 c¨

N
H , and I-I3c/N
H3C , 3 In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -C(0)NR9R19.
In some embodiments, in each of Formulas (II.a.), (ll.ai), and (II.a.2), R2 is -C(0)NH2.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -C(0)NR9R19, wherein R9 and R19 can be the same or different, each being independently selected from alkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is -C(0)NR9R19, wherein R9 is unsubstituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)NR9R19, wherein R9 is substituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is ¨
C(0)NR9R19, wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R19 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)137. --C(0)0R8, and -C(0)NR9R19.
Non-limiting exarnples of R2 include the following moieties:

A
-,,,, cF3, 0--cHF2, , , --( ---\h 1,4),v, -i4).0H Y%
.f`rµ

.1 114 0 OTh AV--LO .Yo OH , OH I
¨
( ..nr t o 0.1N O
.4 j'll 0 i .11.4W
12)( kl LI
rari2 NH2 Nry NH2 , 0 , ,NH , sr NH
,ro H 0 0 0 etj. " '6:- 0 :c _ : 15L

H2N H2N H2N , ' d.r.e 0o ss %AP S1/4c._ NH0 ch .V6O Cr NH NH NH
H2N( H2N
(3)6 H2No ) , NH2 N , N , NH ,O
=
OrNNTh "sY0 0 N
NH, H, and \
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is o CF3.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is \-)*.
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is `t.
=
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is N
In some embodiments, in each of Formulas (II.a.), (II.a.1), and (II.a.2), R2 is In one embodiment, the compounds of the invention have a structure shown in Formula (II.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:
=
)7--- X
N

(II.b.) wherein X, R1, R2, E, and ring B are selected independently of each other and wherein:
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R5)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0R8)-, -N(C(Y)N(R9)(1110))-.

ring B is a substituted or unsubstituted heteroaromatic ring;
and X, Ri, R2, R4, R6, R6, R7, R8, R9, R", Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I).
In one embodiment, Formula (II.b.) has the general structure shown in Formula (II.b.1):

N

(II.b.1).
In one embodiment, Formula (II.b.) has the general structure shown in Formula (II.b.2):
W
X

N

(II.b.2).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), X is S.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), X is S(0).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), X is 8(0)2.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -C(R4)(R6)-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (II.b), (11b.1), and (II.b.2), E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected .
from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -0-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -S-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -S(0)-.
In some embodiments, in each of Formulas (II.b), (10..1), and (II.b.2), E is -S(0)2-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -C(R4)(1:16)-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -N(R6)-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -1\1(C(Y)137)-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -N(C(Y)0118)-.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), E is -N(C(Y)N(R9)(R10))-.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Y is (.0).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Y is (=S).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Y is (=N(R13)).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Y is (=N(CN)).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Y is (=N(0R14)).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Y is (=N(R15)(R16)).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Y is (=C(R17)(R18)).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an unsubstituted heteroaromatic ring.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an .
unsubstituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2.
In some embodiments, in each of Formulas (II.b), (l1.b.1), and (II.b.2), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0C(0)0R2 , -NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and ¨NR23C(0)NR25R26.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (Il.b.2), B is a 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR251:126, _c(0) R24, -C(0)0R29, -S R19, -S(0) R19, -S02R19, -0C(0) R24, -C(0)N R25R26, -NR23C(N-CN)NR25R26 and ¨NR23C(0)NR25R26.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is a 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substiluent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R13, -0C(0)01:126, -NR21=-=22, _ "
NR¨SO2R24, -NR23C(0)0R23, -NR23C(0)R24, -S02N1325R26, -C(0)R24, -C(0)013213, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and ¨
NR23C(0)NR25R26.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and O.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is a 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom = - :.being independently selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0F116, -NR21R22, _c(o)R24., -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, and -C(0)NR25R26.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an unsubstituted 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -N11211=122, -NR23S021324, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, -C(0)1124, -C(0)01320, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR251:126 and -NR23C(0)NR251326.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an unsubstituted 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and O.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is a 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -01:119, -NR21R22, _c(0)-24, C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, and -C(0)NR25R26.
-= In some embodiments, in-each of Formulas (II.b), (II.b.1), and (II.b.2), B
is a 5-membered heteroaromatic ring having S as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0R19, -NR21R22, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, and -C(0)NR25R26.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom.
In one embodiment, Formula (II.b.) has the general structure:

X
X /6v s N N
R 2 or R2 In one embodiment, Formula (II.b.) has the general structure:
W
X) s N N
=
R2 or R2 In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R1 is unsubstituted aryl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R1 is unsubstituted phenyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R1 is 1 0 unsubstituted naphthyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), RI is substituted aryl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R1 is substituted phenyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), RI is substituted naphthyl.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R1 is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R20, -SRI , -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), I:11 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group =
consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R20, -SRI , -S(0)R16, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO2, -NR21R22, and haloalkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R1 is selected from the group consisting of:
=

halo /-h halo NS, õ/õ.r.j halo S.\ I halo ab .1"Prj ____________________ halo __________ halo SPrj , and .r.rjj .
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R1 is:
perfluoroaIk /-\
halo In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), RI is phenyl substituted with one to three fluoro groups.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), 111 is phenyl substituted with two fluoro groups.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), RI is phenyl substituted with one fluoro group.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), RI
is:
F F
J."
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is -C(Z)R7.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is -C(Z)NR91:00.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is -C(Z)0R8.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is -S02NR8R10.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is alkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is heteroalkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is aryl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is heteroaryl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is cycloalkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is cycloalkenyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is heterocycloalkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is heterocycloalkenyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Z is (=0).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Z is (=S).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Z is (=N(R13)).
In some ernbodiments, in each of Formulas (Il.b), (II.b.1), and (II.b.2), Z is (=N(CN)).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Z is (=N(0R14)).

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Z is (=N(R15)(R16)).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), Z is (=C(R17)(R16)).
In some embodiments, in each of Formulas (Il.b), (II.b.1), and (II.b.2), R2 is -C(Z)R7, and Z is (=0).
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)H.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)alkyl.
In knila embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)CH3.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)R7, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R2 , -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, -SRI , -S(0)F11 , -SO2R19, -0C(0)R24, -C(0)NR251:126, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)F17, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -0R19, -NIR21R22, and cycloalkyl.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)R7, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)1R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH2, and cyclopropyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)R7, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each.substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)R7, wherein said R7 is alkyl substituted with -OH.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)117, wherein said R7 is unsubstituted heterocycloalkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)R7, wherein said R7 is substituted heterocycloalkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)1=17, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02N1R25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)1,4R25R26, u(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (11b), (II.b.1), and (II.b.2), R2 is -C(0)R7, wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.
In some embodiments, in each of Formulas (11.b), (II.b.1), and (II.b.2), R2 is selected from:
II II -¨c¨

H3C , and H3c In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is -C(0)NR9R19.
In some embodiments, in each of ForrinUlas (II.b), (II.b.1); and (11.11.2), R2 is -C(0)NH2.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is -C(0)NR9R19, wherein R9 and R19 can be the same or different, each being independently selected from alkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is -C(0)NR9R16, wherein R9 is unsubstituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (II.b), (11.b.1), and (II.b.2), R2 is -C(0)NR9R19, wherein R9 is substituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is ¨
C(0)NR9R10, wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R1 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)F17. ¨C(0)0119, and -C(0)NR9R10.
Non-limiting examples of R2 include the following moieties:

,r,f1 ..Ni J=rt t--.µ A
L.... 0_, , , , cF3, 0 CHF2, F-ja.c.,1tri*, 0.-N, sr_r(0 ..ssi. '''.:A0 ) , HO
iir 69s-1 \ 0 O

0 .. \ 0 ....r,L7c, t."..
o lk, ,.o , OH , OH , l , , "to (Yjsil d'll i NH
--2 , NH 2 , s, .r, , ..õõ, 0 "
HN,õ..õ0 HNN,--NH O
jro r I H , o'.11,-NH2 jl 62N H2N H2N , H
NW
c_:700.' ' ' C ' 3#
, FIN , H2N , H2N

1.0 tPre r(t.0 jj3-c&
NH NH 1.12N(S) , 1 ) H2N H2N , NH2 , N NH , o C) 0 C-7 , Cr>I , and o 0 NH, In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is v.
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is H
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is `z, In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is =
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is I .
In some embodiments, in each of Formulas (II.b), (II.b.1), and (II.b.2), R2 is - In one embodiment, the compounds of the invention have a structure shown in Formula (111.1) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:
R1\ X
(R3) (111.1) wherein X, R1, R2, R3, p, E, and ring B are selected independently of each other and wherein:
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0R8)-, and -N(C(Y)N(R8)(R1 ))-; and p is 0, 1, or 2; and ring B, X, RI, R2, Ra, R5, Rs, R7, R8, Rs, R10, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (1).
In one embodiment, in Formula (111.1):
E is selected from the group consisting of -C(R4)(R6)-, -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-;
ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2, said substituents.on said aromatic ring or said heteroaromatic ring (when present) be.ingiridependently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0C(0)0R2 , -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR261:126, -C(0)R24, -C(0)0R20 , -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26;
RI is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR261=126, -C(0)R24, -C(0)0R20, -SRI9, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR261:126, -NR23C(N-CN)NR261126 and -NR23C(0)NR26R26;
R2 is selected from the group consisting of -C(0)R7, -C(0)NR9R10, and -C(0)01=18;
p is 0 or 1; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R10, -0C(0)0F126, -N R21R22, -C(0)R24, -C(S)R24, -C(0)0R26, and -C(0)NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)01326, -N R21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR26R26, -C(0)R24, -C(0)0R26, -S1316, -S(0)R16, -SO2R13, -0C(0)R24, -C(0)NR261326, -NR23C(N-CN)NR26R26 and -NR23C(0)NR
5R26.
In one embodiment, in Formula (111.1):
ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxaz.olyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl;
1:11 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR2IR22, and haloalkyl;
R2 is selected from the group consisting of -C(0)R7, -C(0)NR61:116, and -C(0)0116;
p is 0 or 1; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR211322, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR25R26.
In one such embodiment, in Formula (111.1):
R1 is:
F F
=
'=
;and R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, the compounds of the invention have a structure shown in Formula (111.2) and include pharmaceutically acceptable'salts, solvates, esters, prodrugs, or isomers of said compounds:

N, E

(F13) (111.2) wherein X, R1, R2, R3, p, E, and ring B are selected independently of each other and wherein:

E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R5)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0R6)-, and -N(C(Y)N(R9)(R10))-; and p is 0, 1, or 2, and ring B, X, R', R2, R4, R5, R6, R7, R8, R9, R19, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I).
In one embodiment, in Formula (111.2):
E is selected from the group consisting of -C(R4)(R5)-, -0-, -S-, -S(0)-, -5(0)2-, and -N(R6)-;
ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2, said substituents on said aromatic ring or said heteroaromatic ring (when present) being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -01119, -0C(0)0R29, -NR21 -22, R NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
R1 is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR', -S(0)1319, -S021119, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;

R2 is selected from the group consisting of -C(0)R7, -C(0)NR9R1 , and -C(0)0R8;
p is 0 or 1; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R20, -NR21R22, -C(0)R24, -C(S)R24, -C(0)0R20, and -C(0)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (111.2):
ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl;
R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloa141;
R2 is selected from the group consisting of -C(0)R7, -C(0)NR91110, and -C(0)0R9;
p is 0 or 1; and each 113 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21e, -NR23s02R24, -NR23o(0)0R20, -NR23o(o)R24, -s02NR25R26, -o(o)R24, -o(0)0R20, -se, _s(o)e, -s02e, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26.
In one such embodiment, in Formula (111.2):
= ..
R1 is:
F 4.1 F
;and R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R26, and -C(S)R24.
In one embodiment, the compounds of the invention have a structure shown in Formula (III.a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:
R' 411) R3) N A

(III.a.) wherein X, R1, R2, R3, p, E, ring A, and ring B are selected independently of each other and wherein:
ring A (including E and the unsaturation shown) is a 5-membered cycloalkenyl or heterocycloalkenyl ring;
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0118)-, -N(C(Y)N(R9)(R19))-, -C(0)-N(1111)-, -N(R")-C(0)-, -S(0)2-N(R")-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, and -C(117)=N-;
ring B is a substituted or unsubstituted aromatic ring;
p, X, R1, R2, R3, Fe, R6, R6., R7, R8, R9, R19, R",1312, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I).
In one embodiment, Formula (III.a) has the general structure:

N R

In one embodiment, Formula (III.a) has the general structure:

R3) - A-N
¨
1:12 In one embodiment, in Formula (III.a.), p is 0, 1, or 2;
In one embodiment, in Formula (III.a.), X is -S-.
In one embodiment, in Formula (III.a.), X is -S(0)-.
In one embodiment, in Formula (III.a.), X is -S(0)2-..
In one embodiment, in Formula (III.a.), ring A is a cycloalkenyl ring and E is -C(R4)(R6)-.
In one embodiment, in Formula (III.a.), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S.(0)2-, -C(0)-0-, -0-C(0)-,10-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, and -C(R7)=N-. By way of non-limiting illustration, an example of a compound of Formula (III.a.) wherein E is -C(0)-N(R11)-io *
NN NH
includes: o .
In one embodiment, in Formula (III.a.), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In one embodiment, in Formula (III.a.), E is selected from the group consisting of -0-, -S-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.

In one embodiment, in Formula (III.a.), E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R".
In one embodiment, in Formula ((11.a.), E is -0-.
In one embodiment, in Formula (III.a.), E is -S-.
In one embodiment, in Formula (111.a.), E is -S(0)-.
In one embodiment, in Formula (III.a.), E is -S(0)2-=
In one embodiment, in Formula (III.a.), E is -C(R4)(R6)-.
In one embodiment, in Formula (III.a.), E is -N(R6)-.
In one embodiment, in Formula (III.a.), E is -N(C(Y)R7)-.
In one embodiment, in Formula (III.a.), E is -N(6(Y)01:0-.
In one embodiment, in Formula (III.a.), E is -N(C(Y)N(R9)(R10))_.
In one embodiment, in Formula (III.a.), E is -C(0)-N(R11)-.
In one embodiment, in Formula (III.a.), E is -N(R11)-C(0)-.
In one embodiment, in Formula (III.a.), E is -S(0)2-N(R11)-.
In one embodiment, fn Formula (III.a.), E is -N(R1)-S(0)2-=
In one embodiment, in Formula (III.a.), E is -C(0)-0-.
In one embodiment, in Formula (111.a.), E is -0-C(0)-.
In one embodiment, in Formula (III.a.), E is -0-N(R6)-.
In one embodiment, in Formula (III.a.), E is -N(R6)-0-.
In one embodiment, in Formula (III.a.), E is -N(R6)-N(R12)-.
In one embodiment, in Formula (III.a.), E is -N=N-.
In one embodiment, in Formula (III.a.), E is -C(137)=N-.
In one embodiment, in Formula (III.a.), Y is (=0).

In one embodiment, in Formula (111.a.), Y is (=S).
In one embodiment, in Formula (III.a.), Y is (=N(R13)).
In one embodiment, in Formula (III.a.), Y is (=N(CN)).
In one embodiment, in Formula (III.a.), Y is (=N(0R14)).
In one embodiment, in Formula (III.a.), Y is (=N(R15)(R16)).
In one embodiment, in Formula (III.a.), Y is (=C(1317)(R18)).
In one embodiment, in Formula (III.a.), B is an unsubstituted aromatic ring.
In one embodiment, in Formula (III.a.), B is an unsubstituted benzo ring, and Formula (III.a.) has the general structure:

\)-1--- X
R3) N A
R2 = =
In one embodiment, in Formula (III.a.), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02N R25-H _263 C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR291326, -NR23C(N-CN)NR25R29 and -NR23C(0)NeR29.

In one embodiment, in Formula (III.a.), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR261:126,_ )11 C(0)0R26, -SR", -S(0)R16, -SO2R16, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR261:126 and -NR23C(0)NR26R26.
In one embodiment, in Formula (III.a.), R1 is unsubstituted aryl.
In one embodiment, in Formula (III.a.), R1 is unsubstituted phenyl.
In one embodiment, in Formula (III.a.), R1 is unsubstituted naphthyl.
In one embodiment, in Formula (III.a.), R1 is substituted aryl.
In one embodiment, in Formula (III.a.), R1 is substituted phenyl.
In one embodiment, in Formula (III.a.), R1 is substituted naphthyl.
In one embodiment, in Formula (III.a.), R1 is aryl substituted with one or.rnore substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, _NR23s02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR261:126, -C(0)R24, -C(0)0R26, -SR19, -S(0)R16, -SO2R16, -0C(0)R24, -C(0)NR261126, _N
L(NI-CN)NR25R26 and -NR23C(0)NR26R26.
In one embodiment, in Formula (111.a.), R1 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR", -0C(0)01326, -NR21 R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR251:126 and -NR23C(0)NR25R2e.
In one embodiment, in Formula (III.a.), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO2, -NR21R22, and haloalkyl.
In one embodiment, in Formula (III.a.), R1 is selected from the group consisting of: -haloõ...4..- HO.õ,...4 ______ NC,,,./.....- 02N..,.../..__--, µ\ / _____________ halo k, / __ halo S / __ halo / __ halo ...r.f haloalkyl.,4õ
(N\ /halo . S ____ / halo ..
=
:Pr.( ,and rrj's .
In one embodiment, in Formula (III.a.), 1:11 is:
perfluoroallryl.õ4.-_____________________ halo In one embodiment, in Formula (III.a.), R1 is phenyl substituted with one to three fluoro groups.
In one embodiment, in Formula (III.a.), R1 is phenyl substituted with two fluoro groups.

In one embodiment, in Formula (III.a.), R1 is phenyl substituted with one fluoro group.
In one embodiment, in Formula (III.a.), R1 is:
F F
In one embodiment, in Formula (III.a.), R2 is -C(Z)R7.
In one embodiment, in Formula (III.a.), R2 is -C(Z)NR9R10.
In one embodiment, in Formula (III.a.), R2 is -C(Z)0R8.
. In one embodiment, in Formula (III.a.), R2 is -S02NR9R10.
In one embodiment, in Formula (III.a.), R2 is alkyl.
In one embodiment, in Formula (III.a.), R2 is heteroalkyl.
In one embodiment, in Formula (III.a.), R2 is aryl.
In one embodiment, in Formula (III.a.), R2 is heteroaryl.
In one embodiment, in Formula (III.a.), R2 is cycloalkyl.
In one embodiment, in Formula (III.a.), R2 is cycloalkenyl.
In one embodiment, in Formula (III.a.), R2 is heterocycloalkyl.
In one embodiment, in Formula (III.a.), R2 is heterocycloalkenyl.
In one embodiment, in Formula (III.a.), Z is (=0).
In one embodiment, in Formula (III.a.), Z is (=S).
In one embodiment, in Formula (III.a.), Z is (=N(R13)).
In one embodiment, in Formula (III.a.), Z is (=N(CN)).
In one embodiment, in Formula (III.a.), Z is (=N(OR")).

In one embodiment, in Formula (III.a.), Z is (=N(R15)(R16)).
In one embodiment, in Formula (III.a.), Z is (=C(R17)(R18)).
In one embodiment, in Formula (III.a.), R2 is -C(Z)R7, and Z is (=0).
In one embodiment, in Formula (III.a.), R2 is ¨C(0)H.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)alkyl.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)CH3.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)117, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R15, -0C(0)0R26, -NR21 R22, -NR23S021324, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR16, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)137, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -0R16, -NR21R22, and cycloalkyl.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)R7, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.
In one embodiment, in Formula (l11.a.), R2 is ¨C(0)117, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NIH2, and cyclopropyl.

In one embodiment, in Formula (III.a.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with -OH.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)R7, wherein said 1:17 is unsubstituted heterocycloalkyl.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)R7, wherein said R7 is substituted heterocycloalkyl.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)R7, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NIR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR26 C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR261126, -NR230(N-CN)NR26R26 and -NR23C(0)NR261126.
In one embodiment, in Formula (III.a.), R2 is ¨C(0)117, wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.

In one embodiment, in Formula (III.a.), R2 is selected from:
II ¨
I ___________________________________________ II
c ,-n¨c¨

H3eN _________________________ , and H/
In one embodiment, in Formula (III.a.), R2 is -C(0)NR9R10.
In one embodiment, in Formula (III.a.), R2 is -C(0)NH2.
In one embodiment, in Formula (III.a.), R2 is -C(0)NR91310, wherein R9 and R1 can be the same or different, each being independently selected from alkyl.
In one embodiment, in Formula (III.a.), R2 is -C(0)NR9R10, wherein R9 is unsubslituted heterocycloalkyl and R1 is selected from the group consisting of H
-.and alkyl.
In one embodiment, in Formula (III.a.), R2 is -C(0)NR9R10, wherein R9 is substituted heterocycloalkyl and R1 is selected from the group consisting of H
and alkyl.
In one embodiment, in Formula (III.a.), R2 is -C(0)NR9R1 , wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and Rw is selected from the group consisting of H and alkyl. =
In one embodiment, in Formula (III.a.), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)R7. -C(0)0R8, and -C(0)NR9R10.
In one embodiment, in Formula (III.a.), R2 is selected from the group consisting of .t.pr.L \)H4Aõ3 1- CHF2 0 F3L,.¨ 0 0, V1L'r ......\
0===-= , 0 , \--11-v, õ4õ..1OH Nrko .,..).õ0-...
,HO
,, .rr\
0"--)., .,,,, >...\/.

,...
I
syko 7.1),c, (1 0O
0.. , OH , OH , 122, N
, , ' ¨
..rsrto A
NH2 il ((:$
1,(K--- NH2 , NH2 , ,N.s........-.
, 0 , ,NH, rrisj 0j) 0j1.,r. NH2 Lr.0 N ,...--- NH Ot HN.-- & () J) HNN-C) Fl ------f I
H2N , H2N , H2N , , , . H 0 , 0 = 112N --Ci-k ,H2N
, HN
' SSIS rr, ,,,,,,.
0 0 eo0 .c:(:) NH NH NH NH
C( H N(57 :
, 2 H R
, 2 , .rr --0 .µ,..
oJ.) Lo /o , H2N4'---1 H , .H2 , N , N , NH , c,, .n.... .,e, .1^
aDNI,) Oj o /
A \
r'NNt-) ....,0 0 NH ci:74 O.T.3 c4:).1 , and \ rr< 14¨

, / =
, In one embodiment, in Formula (III.a.), R2 is `2. 0..
3.

In one embodiment, in Formula (III.a.), R2 is VjL\-----.

----a'V
In one embodiment, in Formula (III.a.), R2 is \ .

,..)-..,...,OH
In one embodiment, in Formula (III.a.), R2 IS %
0 = - .
1.)0 -. .
In one embodiment, in Formula (III.a.), R2 IS '23 In one embodiment, in Formula (III.a.), R2 is z 2.

A --\ N
In one embodiment, in Formula (III.a.), R2 is I . =

,A-- \
lik N¨( N¨

In one embodiment, in Formula (III.a.), R2 is __ I / .
In one embodiment, in Formula (III.a.), p is 0 and R3 is not present.
In one embodiment, in Formula (III.a.), p is 1.
In one embodiment, in Formula (III.a.), p is 2.
In one embodiment, in Formula (III.a.), p is 3.
In one embodiment, in Formula (III.a.), p is 4.

In one embodiment, in Formula (III.a.), p is > 2 and at least two groups R3 are attached to the same ring atom.
In one embodiment, in Formula (III.a.), p is 1 and R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.a.), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R23, =
-NR21R22, -NR23S021=124, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -00(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.a.), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein each 113, which may be the same or different, is independently selected from the group consisting of alkyl; =
heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0C(0)01:126, -N R21 R22, _N R23s02 R24, _N
L,(0)0R2 , -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)1113, -S021:112, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.a.), p is 2, 3, or 4 and at least two groups 1:13 are bound to the same ring carbon atom, wherein two R3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.

In one embodiment, in Formula (111.a.), p is 1 or 2 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R20, _NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -S02NeR26, -C(0)R24, -C(S)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26, -NR23C(0)NR25R26, and -NRz3-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloallvnyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R23, -NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR25R26, _c(0)R24, -C(0)0R23, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NIR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.a.), p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and =
each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21e, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -SO2NR25R26, _c(0)R24, -C(0)0R23, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NIR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.a.), p is 2 and any two R3 groups bound to the same ring A atom are taken together to form a -C(0)- group.

In one embodiment, in Formula (III.a.), p is 2 and any two R3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, 0, S, S(0), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2.
In one embodiment, in Formula (III.a.), R3 is alkyl.
In one embodiment, in Formula (III.a.), R3 is heteroalkyl.
In one embodiment, in Formula (Ill.a.), R3 is alkenyl.
In one embodiment, in Formula (III.a.), R3 is heteroalkenyl.
In one embodiment, in Formula (III.a.), R3 is alkynyl.
In one embodiment, in Formula (III.a.), R3 is heteroalkynyl.
In one embodiment, in Formula (III.a.), R3 is aryl.
In one embodiment, in Formula (III.a.), R3 is heteroaryl.
In one embodiment, in Formula (111.a.), R3 is cycloalkyl.
In one embodiment, in Formula (III.a.), R3 is cycloalkenyl.
In one embodiment, in Formula (III.a.), R3 is heterocycloalkyl.
In one embodiment, in Formula (III.a.), R3 is heterocycloalkenyl.
In one embodiment, in Formula (III.a.), R3 is halogen.
In one embodiment, in Formula (III.a.), R3 is ¨CN.
In one embodiment, in Formula (III.a.), R3 is -NO2.
In one embodiment, in Formula (III.a.), R3 is -01r.
In one embodiment, in Formula (III.a.), R3 is -0C(0)0R26.
In one embodiment, in Formula (III.a.), R3 is -NR21R22,.
In one embodiment, in Formula (III.a.), R3 is -NR23S02R24.

In one embodiment, in Formula (III.a.), R3 is -NR23C(0)0R26.
In one embodiment, in Formula (III.a.), R3 is -NR23C(0)R24.
In one embodiment, in Formula (III.a.), R3 is -SO2NR25R26.
In one embodiment, in Formula (III.a.), R3 is -C(0)R24.
In one embodiment, in Formula (III.a.), R3 is -C(0)0R25.
In one embodiment, in Formula (III.a.), R3 is -SR".
In one embodiment, in Formula (III.a.), R3 is -S(0)R15.
In one embodiment, in Formula (III.a.), R3 is -S02R13,.
In one embodiment, in Formula (III.a.), R3 is -0C(0)R24.
In one embodiment, in Formula (III.a.), R3 is -C(0)NR25R26,.
In One embodiment, in Formula (III.a.), R3 is -NR23C(N-CN)NR25R26.
In one embodiment, in Formula (III.a.), R3 is ¨NR23C(0)NR25R26.
In one embodiment, in Formula (III.a.), R3 is selected from the group consisting of: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl Jj1 (straight or branched), phenyl, N, N, NH2, H2N H2N
SPrr ~IV"
LLOH
=AAIV% %ANN, OH

1? ~AI
NH2 HN HN\
HN)r¨NH 2 I) = = OH
1.1_ HN
N HN
, o , , 0 OH , and In one embodiment, in Formula (III.a.), when E is -NR6-, R3 is absent.
In one embodiment, Formula (III.a.) has the general structure (III.a.1):

- (R3) (III.a.1) wherein X, R1, R2, R3, p, E, and ring B are selected independently of each other and wherein:
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R5)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0118)-, and -N(C(Y)N(R9)(R10))-;
and p, X, RI, R2, R3, R4, R5, R6, R7, 1:18, R9, Rw, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (III.a.).

In one embodiment, Formula (III.a.1) has the general structure shown in Formula (111.a.1.1):

X
N
E
( R3 ) (111.a.1.1).
In one embodiment, Formula (111.a.) has the general structure III.a.2:
W
4-- X 40) N
112 (R3)p . =
(111.a.2) wherein X, R1, R2,1:33, p, E, and ring B are selected independently of each other and wherein:
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R5)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0R8)-, and -N(C(Y)N(R9)(R19))-;
and p, X, R1, R2,1:13, R4, R5, R6, R7, R5, R9, R19, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (III.a.).

In one embodiment, Formula (III.a.2) has the general structure shown in Formula (III.a.2.1):

X
N
I"
R2 (R3L
(III.a.2.1).
In one embodiment, Formula (III.a.2) has the general structure shown in Formula (III.a.2.2):

N
E
R2 (R3 ) (III.a.2.2).

In one embodiment, Formula (III.a.2) has the general structure shown in Formula (III.a.2.3):
R
)7---"X
N
IE
R2 (R3 ) (III.a.2.3).
In one embodiment, Formula (III.a.2) has the general structure shown in Formula (III.a.2.4):

x, 400 N
= E
12(R -3-), (III.a.2.4).
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.3), and (III.a.2.4), p is 0.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4), p is 1.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4), p is 2.

In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (Ill.a.2.3), and (III.a.2.4),E is -C(R4)(116)-.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (Ill.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2A),E is selected from the group consisting of -0-and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (III.a.1), (111.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -0-.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -S-.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -S(0)-.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -S(0)2-=
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -C(R4)(R5)-.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -N(R6)-.
In some embodiments, in each of Formulas (III.a.1), (Ill.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -N(C(Y)R7)-.

In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -N(C(Y)0R8)-.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),E is -N(C(Y)N(R8)(R16))-.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),Y is (=0).
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),Y is (=S).
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),Y is (=N(R13)).
In some.eMbodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),Y is (=N(CN)).
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),Y is (=N(0R14)).
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),Y is (=N(R15)(R16)).
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),Y is (=C(R17)(R18)).
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloalkyl.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),R1 is selected from the group consisting of:

Haq NC.¨ 021,1õ.1c¨

/ _________________ halo \ / __ halo \ / __ halo \ / ___ halo alkyl __________________ halo ____________ halo ,and .
In one embodiment, in Formula (I), 1:11 is:
perfluoroalkyl-______________________ halo In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (Ill.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),R1 is phenyl substituted with one to three fluoro groups.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),R1 is phenyl substituted with two fluoro groups.
In some ernbodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),R1 is phenyl substituted with one fluoro group.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (l11.a.2.4),R1 is:
F
PCS.' In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),R2 is selected from the group consisting of:
alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)F17. ¨C(0)0R8, and -C(0)NR8R10.

In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),R2 is selected from the group consisting of:

sist 0 0 .prv . I' \,)( cF3, 0 cHF2 . , o's\, jf jiss. o 0 ''(0 0 T 0 ..õ(11õ..,4314 -,---,0 õ...1.L.,o ..1`rµ

..1 5.f.X0 ...sr_Lo ,./.._\c, )_____µ n Lo _ .,,,,,N/

µ 2 ....A.0 2 , OH , OH , I
, , (C:1 1 \--"IL-----^pdu 1.112 NH2 , mi2NH2 , ,N,........
, 0NH
, , 05:11, 0 jr.0 0j) 0j) -"PAP
0 '(::L
liN,ro HNy,NH H Hp.....
0(1--:j.''' , H2N , H2N , vS
.c1Prri 0 -Picr() '''cl&o j'jc& ct) 6Pf:0 NH 4 4-:
, H2 , , , rr 1121ti H2N , NH2 , ,Les o H

I .
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.3), and (III.a.2.4),p is 1 or 2 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R25, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, _c(os=-=)1124, C(S)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, rt u(N-CN)NR25R26, -NR23C(0)NR25R26, and -NR23-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02N1R25R26, -C(0)R24, -C(0)0R25, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NIR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, _C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),p is 2 and any two R3 groups bound to the same ring A atom are taken together to form a ¨C(0)- group.
In some embodiments, in each of Formulas (III.a.1), (III.a.1.1), (III.a.2), (III.a.2.1), (III.a.2.2), (III.a.2.3), and (III.a.2.4),p is 2 and any two R3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2.
=
In one embodiment, the compounds of the invention have a structure shown in Formula (III.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:

R3) N A

wherein X, R1, R2, R3, p, E, ring A, and ring B are selected independently of each other and wherein:

ring A (including E and the unsaturation shown) is a 5-membered cycloalkenyl or heterocycloalkenyl ring;
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)0R8)-, -N(C(Y)N(R9)(R16))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, and -C(117)=N-;
ring B is a substituted or unsubstituted heteroaromatic ring;
and p, X, R1, R2,1=13, R4,1:16, R6, R7, R8, R9, R1 , R11, R12, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I).
In one embodiment, Formula (III.b) has the general structure:
W
OM
N R3) In one embodiment, Formula (III.b) has the general structure:
)7__x 410 R3) -- A
N
I

In one embodiment, in Formula p is 0, 1, or 2.

In one embodiment, in Formula (111.b.), X is S.
In one embodiment, in Formula (III.b.), X is S(0).
In one embodiment, in Formula (III.b.), X is S(0)2.
In one embodiment, in Formula (III.b.), ring A is a cycloalkenyl ring and E is -C(R4)(R5)-.
In one embodiment, in Formula (111.11), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, and -C(R7)=N-. By way of non-limiting illustration, an example of a compound.of Formula (III.a.) wherein E is -C(0)-N(R11)-1111'111 S

N_N NH
includes:
In on embodiment, in Formula (III.b.), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In one embodiment, in Formula (III.b.), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In one embodiment, in Formula (III.b.), E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In one embodiment, in Formula (III.b.), E is -0-.
In one embodiment, in Formula (III.b.), E is -S-.
In one embodiment, in Formula (III.b.), E is -S(0)-.

In one embodiment, in Formula (III.b.), E is -S(0)2-.
In one embodiment, in Formula (III.b.), E is -C(R4)(R6)-.
In one embodiment, in Formula (III.b.), E is -N(R6)-.
In one embodiment, in Formula (III.b.), E is -N(C(Y)1=17)-.
In one embodiment, in Formula (III.b.), E is -N(C(Y)01:18)-.
In one embodiment, in Formula (III.b.), E is -N(C(Y)N(R6)(R16))-.
In one embodiment, in Formula (III.b.), E is -C(0)-N(R11)-.
In one embodiment, in Formula (III.b.), E is -N(R11)-C(0)-.
In one embodiment, in Formula (III.b.), E is -S(0)2-N(R11)-.
In one embodiment, in Formula (III.b.), E is -N(R11)-S(0)2--In one embodiment, in Formula (III.b.), E is -C(0)-0-.
In one embodiment, in Formula (III.b.), E is -0-C(0)-.
In one embodiment, in Formula (III.b.), E is -0-N(R6)-.
In one embodiment, in Formula (III.b.), E is -N(R6)-0-.
In one embodiment, in Formula (III.b.), E is -N(R6)-N(R12)-.
In one embodiment, in Formula (III.b.), E is -N=N-.
In one embodiment, in Formula (III.b.), E is -C(R7)=N-.
In one embodiment, in Formula (III.b.), Y is (.0).
In one embodiment, in Formula (III.b.), Y is (=S).
In one embodiment, in Formula Y is (=N(R13)).
In one embodiment, in Formula (III.b.), Y is (=N(CN)).
In one embodiment, in Formula (111.b.), Y is (=N(0R14)).
In one embodiment, in Formula (III.b.), Y is (=N(R15)(R16)).
In one embodiment, in Formula (III.b.), Y is (=C(R17)(R18)).

In one embodiment, in Formula (III.b.), B is an unsubstituted heteroaromatic ring.
In one embodiment, in Formula (III.b.), B is an unsubstituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2.
In one embodiment, in Formula (III.b.), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R13, -0C(0)0R26, -N R21 R22, -NR23S02R24, -NR23C(0)0R26, -NIR23C(0)R24, -302N R25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S021:119, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26.
In one embodiment, in Formula (III.b.), B is a 5-6-membered heteroaromatic ring having from 1-3 ring heteroatonns, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -01113, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R13, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.

In one embodiment, in Formula (III.b.), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In one embodiment, in Formula (III.b.), B is a 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, _NR23s02R24, 11 L,(0)0R2 , -NR23C(0)R24, -S02NR251=126, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R
26, L,(N-CN)NR25R25 and ¨NR23C(0)NR25R26.
In one embodiment, in Formula (III.b.), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and O.
In one embodiment, in Formula (III.b.), B is a 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, , , , _oRis _NR21R22 _c(0)R24 heteroalkyl, haloalkyl, -C(0)0R29, -S(0)R19, -SO2R19, -0C(0)R24, and -C(0)NR25R26.

In one embodiment, in Formula (III.b.), B is an unsubstituted 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In one embodiment, in Formula (III.b.), B is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, 9, -0 C (0) 0 R29, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -502NR251126, -C(0)R24, -C(0)0R26, -S(0)R15, -S02R16, -0C(0)R24, -C(0)NR25R26, -IVR23C(N-CN)NFt25R26 and ¨NR23C(0)NR25R26.
In one embodiment, in Formula (III.b.), B is an unsubstituted 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and O.
In one embodiment, in Formula (110.), B is a 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -01419, -NR21R22, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, and -C(0)NR29R26.
In one embodiment, in Formula (111.13.), B is a 5-membered heteroaromatic ring having S as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0R19, -NR21R22, )11 C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, and -C(0)NR25R26.
In one embodiment, in Formula (III.b.), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom.
In one embodiment, in Formula (III.b.), B is selected from the group consisting of s ref?
= .10 , and In one embodiment, in Formula (III.b.), R1 is unsubstituted aryl.
In one embodiment, in Formula (III.b.), R1 is unsubstituted phenyl.
In one embodiment, in Formula (III.b.), R1 is unsubstituted naphthyl.
. 15 In one embodiment, in Formula (III.b.), R1 is substituted aryl.
In one embodiment, in Formula (III.b.), R1 is substituted phenyl.
In one embodiment, in Formula (III.b.), R1 is substituted naphthyl.
In one embodiment, in Formula (III.b.), R1 is aryl substituted with one or more substituents, which can be the same or different, each substituent being 20 independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, _N R21-22, _ NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, _c(o)R24, -C(0)0R20, -SR19, 25 -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR22C(N-CN)NR25R26 and _NR23c(0)NR26R26.

In one embodiment, in Formula (III.b.), R1 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -OC (0 )0 R2 , -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, _cps rsps24, _ C(0)0R2 , -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR251:126, -NR23C(N-CN)NR25R26 and -NR23C(0)NR291R26.
In one embodiment, in Formula (III.b.), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO2, -NR21R22, and haloalkyl.
In one embodiment, in Formula (III.b.), R1 is selected from the group consisting of:
.
halo /\ , 1-10,4- NC..,,./...,- 02N /-,,,,, / __ halo ,S / __ halo S __ halo ,S ..: j halo .144.5 , J-Pri alkyl ....I.,- haloalkyl -\µ / halo ...ri ___________________________________ halo Jscsj ' In one embodiment, in Formula (III.b.), R1 is:
perfluoroalkyl -''/
______________________ halo =

In one embodiment, in Formula (III.b.), is phenyl substituted with one to three fluor groups.
In one embodiment, in Formula (III.b.), R1 is phenyl substituted with two fluoro groups.
In one embodiment, in Formula (III.b.), R1 is phenyl substituted with one fluoro group.
In one embodiment, in Formula R1 is:

In one embodiment, in Formula (Mb.), R2 is -C(Z)F17.
In one embodiment, in Formula (III.b.), R2 is -C(Z)NR9R10 .
In one embodiment, in Formula (III.b.), R2 is -C(Z)ORB.
In one embodiment, in Formula (III.b.), R2 is -SO2NR9R1 .
In one embodiment, in Formula (III.b.), R2 is alkyl.
In one embodiment, in Formula (III.b.), R2 is heteroalkyl.
In one embodiment, in Formula (III.b.), R2 is aryl.
In one embodiment, in Formula (11th.), R2 is heteroaryl.
In one embodiment, in Formula (III.b.), R2 is cycloalkyl.
In one embodiment, in Formula (III.b.), R2 is cycloalkenyl.
In one embodiment, in Formula (III.b.), R2 is heterocycloalkyl.
In one embodiment, in Formula (III.b.), R2 is heterocycloalkenyl.
In one embodiment, in Formula (lILL), Z is (=0).
In one embodiment, in Formula (III.b.), Z is (=S).

In one embodiment, in Formula (III.b.), Z is (=N(R13)).
In one embodiment, in Formula (III.b.), Z is (=N(CN)).
In one embodiment, in Formula (III.b.), Z is (=N(0R14)).
In one embodiment, in Formula (III.b.), Z is (=N(R16)(R16)).
In one embodiment, in Formula (III.b.), Z is (=C(R17)(R18)).
In one embodiment, in Formula (III.b.), R2 is -C(Z)137, and Z is (=0).
In one embodiment, in Formula (III.b.), R2 is ¨C(0)H.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)alkyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)CH3.
=
In one embodiment, in Formula (III.b.), R2 is ¨C(0)1R7, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkpyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, --S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)117, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NR21R22, and cycloalkyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)R7, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.

In one embodiment, in Formula (III.b.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH2, and cyclopropyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with -OH.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)R7, wherein said R7 is unsubstituted heterocycloalkyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)R7, wherein said R7 is substituted heterocycloalkyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)R7, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)1:119, -S021:119, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.

In one embodiment, in Formula (III.b.), R2 is ¨C(0)R7, wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.
In one embodiment, in Formula (III.b.), R2 is selected from:
II
_c_ -1-11¨
I N
HC N , and H3c /
In one embodiment, in Formula (III.b.), R2 is -C(0)NR91:11 .
In one embodiment, in Formula (III.b.), R2 is ¨C(0)NH2.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)NR9R10, wherein R9 and R1 can be the same or different, each being independently selected from alkyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)NR9R10, wherein R9 is unsubstituted heterocycloalkyl and R1 is selected from the group consisting of H
and alkyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)NR9R10, wherein R9 is substituted heterocycloalkyl and R1 is selected from the group consisting of H
and alkyl.
In one embodiment, in Formula (III.b.), R2 is ¨C(0)NR9R1 , wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R1 is selected from the group consisting of H and alkyl.
In one embodiment, in Formula (III.b.), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)1R7. ¨C(0)0R8, and -C(0)NR9R10.
In one embodiment, in Formula (lLb.), R2 is selected from the group consisting of -fr'L . is-C F3, CH F2 . -,,,..- =,..,-0 1:)....\ , jsr j::<L .:-'OH, IHO CI , l'Lz-, , .1 \ 0---0 .....õõko ..,4 \---0 0 , \----N-......0 , OH OH 0 , ' NH2 NH2.õ .,,. NH2 , NH2, 0, _NH , , Je.
."

...J.,' OJIjAro HININ.o HN 0 NN 0 N*NH o T. H2N
NH2 r I H

, ' \/Ht , ' ,FIN , H2N , H 2N , .1-rrf sft f= ,P-r cto 9.........
0 .

, .rf .rrl , 0 .,--L
o H2i7i , H2N NH 0 1 C-7'a Cy , 2 , N , N , NH , 0 , (3.1,1 0 jL) o er' )( \
Ci N M Nir--'sNo 0 N

C.--0 0 N C) H 5 Li , H , and .
, In one embodiment, in Formula (III.b.), Ft', is -4 C. 3.
In one embodiment, in Formula (111.b.), 11-o is .
In one embodiment, in Formula (III.b.), R2 is .

In one embodiment, in Formula (III.b.), R2 is 5, In one embodiment, in Formula (III.b..), R2 is `L.

NH

In one embodiment, in Formula (III.b.), Ft' is =
N
In one embodiment, in Formula (III.b.), R2 is I .
0 =
N¨( ¨
In one embodiment, in Formula (III.b.), R2 is .
In one embodiment, in Formula (III.b.), p is 0 and R3 is not present.
In one embodiment, in Formula (III.b.), p is 1.
ln one embodiment, in Formula (III.b.), p is 2.
In one embodiment, in Formula (III.b.), p is 3.
In one embodiment, in Formula (III.b.), p is 4.
In one embodiment, in Formula (III.b.), p is > 2 and at least two groups R3 are attached to the same ring atom.
In one embodiment, in Formula (III.b.), p is 1 and R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (110.), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R20, -NR21e, -NR23so2R24, -NR23copy3R20, -NR23c(0)R24, -so2NR25R26, -c(o)R24, -copy:A-, -SR19, -S(o)R19, -s02R12, -0c(o)R24, -c(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (111.b.), p is 2, 3, or 4 and at legit-two groups R3 are bound to the same ring carbon atom, wherein each R3, which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -01:119, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R2?, -SR19, rS(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.b.), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein two R3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
In one embodiment, in Formula (III.b.), p is 1 or 2 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R20 , -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(S)R24, -C(0)0R2 , -SR19, -S(0)R13, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26, -NR23C(0)NR25R26, and -NR23-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NIR23C(0)0R23, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.b.), p is 1 and 1:13 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, -alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR23S021124, -NR23C(0)0R23, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)01120, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -N1123C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (III.b.), p is 2 and any two 1:13 groups bound to the same ring A atom are taken together to form a -C(0)- group.
In one embodiment, in Formula (III.b.), p is 2 and any two 1:13 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2, or spiroheterocycloalkenyI group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2.
In one embodiment, in Formula (III.b.), R3 is alkyl.
In one embodiment, in Formula (III.b.), R3 is heteroalkyl.
In one embodiment, in Formula (III.b.), R3 is alkenyl.
In one embodiment, in Formula (III.b.), R3 is heteroalkenyl.
In one embodiment, in Formula (III.b.), R3 is alkynyl.
In one embodiment, in Formula (III.b.), R3 is heteroalkynyl.
In one embodiment, in Formula (III.b.), R3 is aryl.
In one embodiment, in Formula (III.b.), R3 is heteroaryl.
In one embodiment, in Formula (III.b.), R3 is cycloalkyl.
In one embodiment, in Formula (III.b.), R3 is cycloalkenyl.
In one embodiment, in Formula (III.b.), R3 is heterocycloalkyl.
In one embodiment, in Formula (III.b.), R3 is heterocycloalkenyl.
In one embodiment, in Formula (III.b.), R3 is halogen.
In one embodiment, in Formula (III.b.), R3 is ¨CN.
In one embodiment, in Formula (III.b.), R3 is -NO2 In one embodiment, in Formula (III.b.), R3 is -0R16.
In one embodiment, in Formula (III.b.), R3 is -0C(0)0R26.
In one embodiment, in Formula (III.b.), R3 is -NR21R22,.
In one embodiment, in Formula (III.b.), R3 is -NR23S02R24.
In one embodiment, in Formula (III.b.), R3 is -NR23C(0)0R26.
In one embodiment, in Formula (III.b.), R3 is -NR23C(0)R24.
In one embodiment, in Formula (III.b.), R3 is -SO2NR25R26.
In one embodiment, in Formula (III.b.), R3 is -C(0)R24.

In one embodiment, in Formula (III.b.), R3 is -C(0)0R26.
In one embodiment, in Formula (III.b.), R3 is -SR19.
In one embodiment, in Formula (III.b.), R3 is -S(0)1:119.
In one embodiment, in Formula (III.b.), R3 is -S02R19,.
In one embodiment, in Formula (III.b.), R3 is -0C(0)R24.
In one embodiment, in Formula (III.b.), R3 is -C(0)NR25R
In one embodiment, in Formula (III.b.), R3 is -NR23C(N-CN)NR25R26.
In one embodiment, in Formula (III.b.), R3 is ¨NR23C(0)NR25R26.
In one embodiment, in Formula (III.b.), R3 is selected from the group consisting of: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl f UN, .rrs'r rrcr (straight or branched), phenyl, N-N, 'N, NH2, H2N H2N
.rf.Pr WV, I 1...) L
OH, oH, ), I , Y-OH, 0 o +sows, HN 1) HNNH2 ,µOH
HN
1)1¨NH2 N J HN HN
0 , o , r, \, 0 OH , and vtrt,u, In one embodiment, in Formula (III.b.), when E is ¨NR6-, R3 is absent.

In one embodiment, Formula (III.b.) has the general structure (III.b.1):

)T- X
N
( R3 ) (III.b.1) wherein X, R1, R2, R3, p, E, and ring B are selected independently of each other and wherein:
Els selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R8)-, -N(R8); -N(C(Y)R7)-, -N(C(Y)0R8)-, and -N(C(Y)N(R8)(R1 ))-;
and p, X, al, R2, R3, R4, R5, R6, R7, 1:18, R9, R.1 , Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (III.b.).

In one embodiment, Formula (III.b) has the general structure shown in Formula (III.b.2):

N
R2 ( R3 )P
(III.b.2) In one embodiment, Formula (III.b) has the general structure shown in Formula (III.b.2.1):
=

N
IE
R2 ( )13 (III.b.2.1).
In one embodiment, Formula (III.b) has the general structure shown in Figure (III.b.2.2):
R
X la) N
R ( R 3 )P
(111 .b.2.2).

In one embodiment, Formula (III.b) has the general structure shown in Formula (III.b.2.3):
R

N
R2 f R3)o (III.b.2.3).
In one embodiment, Formula (III.b) has the general structure shown in Formula (III.b.2.4):

X di N
IE
R2(R-3 )p (III.b.2.4).
In some embodiments, in each of Formulas (III.b.1), (111.112), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),p is 0.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),p is 1.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),p is 2.

In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), E is -C(R4)(R6)-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), E is selected from the group consisting of -0-and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -0-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -S-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -8(0)-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -S(0)2-=
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -C(R4)(R6)-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -N(R6)-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -N(C(Y)R7)-.

In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -N(C(Y)0R8)-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (111.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),E is -N(C(Y)N(R8)(R1 ))-.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),Y is (=0).
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),Y is (=S).
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),Y is (=N(R18)).
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),Y is (=N(CN)).
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (111b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),Y is (=N(0R14)).
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),Y is (=N(R18)(R18)).
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),Y is (=C(R17)(R18)).
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloalkyl.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), al is selected from the group consisting of:

halo /-NC.,q 02NK,.../- halo ___________________ hab / __ halo \ / __ halo \
___________________ halo ________ halo , and In one embodiment, in Formula (I), R1 is:
perIkkoroallryl,4,-_____________________ halo .1=Pr5 In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), RI is phenyl substituted with one to three fluoro groups.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), RI is phenyl substituted with two fluoro groups.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), RI is phenyl substituted with one fluoro group.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), RI is:
F F
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (81.b.2.2), (III.b.2.3), and (III.b.2.4), R2 is selected from the group consisting of:
alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)117. ¨C(0)0R8, and -C(0)NIR9R10.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4), R2 is selected from the group consisting of:

2 jsi;-`1 CH F2 0 0 0 ,f=r\
___ -\,) vkCF3o , F \)*
o'\
, o j::& o ,HO
1.
, .
Sr\
Cr..-1 K

-I
Lo 0 0 \ NI
\ ,...0 co 0 H , OH , , , , ,r-r to OJAI.
(0 I
0(371.1 NH2 , NH2 , , , ,NH
NH2 , ()Ay Jiro HN0 HN HN.. 0 ,,,-- NH o NH2 f I H H , H2N H2N H2N , Cr c) d:
, HN ,H2N ,H2N , Jr ..nc (S)0 ,... 0 0 c 0 ch 0 \ --) NH NH NH NH H2N , H2N
, , .ts sf ,(;0 ,,,--(--- (-,0 Hõ, ,H2N , NH2, N , N , NH , 0,, vv.
0.1.1 (:),..i.õ) 0 ''' ..) /
-t,,AN \
i"'N,- )r\
NH, 0 0.T.34 4 ri , and ' l - .

In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),p is 1 or 2 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R25, -NR"C(0)R24, -S02NR251326, -C(0)R24, -C(S)R24, -C(0)0R25, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26, -NR23C(0)NR25R26, and -NR23-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, hete. haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R25, -NR21R22, -NF123S02R24, -NR23C(0)0R25, -NR23C(0)R24, -S02NR251:126, -C(0)R24, -C(0)0R2 , -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (III.b.1), (III.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R2 , -NR21e, -NR239D2R24, -NR23c(0)0R20, -NR23c(0)F124, -so2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.

In some embodiments, in each of Formulas (III.b.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),p is 2 and any two R3 groups bound to the same ring A
atom are taken together to form a ¨C(0)- group.
In some embodiments, in each of Formulas (III.b.1), (I11.b.2), (III.b.2.1), (III.b.2.2), (III.b.2.3), and (III.b.2.4),p is 2 and any two R3 groups bound to the same ring A
atom are taken together to form a spiroheterocycloalkyl group having from 1 to ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2.
In one embodiment, the compounds of the invention have a structure shown in Formula (IV) and include pharmaceutically acceptable salts, solvtes,.

esters, prodrugs, or isomers of said compounds:

A E
R 3 ) rt R

(IV) wherein X, RI, R2,1=13, p, E, ring A, and ring B and the optional groups attached to ring B are each selected independently of each other and wherein:
E is selected from the group consisting of -C(R4)(1=15)-, -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-;
ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2, said substituents on said aromatic ring or said heteroaromatic ring (when present) being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, _NR23s02R24, -NR23C(0)0R2 , -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)1319, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26;
R1 is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, _NR23s02R24, u(0)0R2 , -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, -S R19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, _NR23c (N-CN)NR251126 and -NR23C(0)NR25R26;
R2 is selected from the group consisting of -C(0)R7, -C(0)NR9R10, and -C(0)0146;
p is 0, 1, or 2; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R2 , -NR21R22, -C(0)R24, -C(S)R24, -C(0)0R20, and -C(0)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -Nee, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -S(0)R16, -SO2R16, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NIR23C(0)NR25R26; and all remaining variables are as defined in each of the embodiments described above in Formula (I).
In one such embodiment, in Formula (IV):
E is selected from the group consisting of -0- and -N(R6)-;
ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl;
R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloalkyl;
R2 is selected from the group consisting of -C(0)R7, -C(0)N1361316, and -C(0)0R6;
p is 0 or 1; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR2,R22, _NR23s02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR251:126, _c(0)R24, -C(0)0R29, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.

In one such embodiment, in Formula (IV);
RI is:
F = F
;and R6 is selected from the group consisting of H, alkyl, -C(0)R24, -C(0)0R23, and -C(S)R24.
In one embodiment, the compounds of the invention have a structure shown in Formula (IV.a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:

R3 )p A

(IV.a.) wherein X, RI, R2, R3, p, E, ring A, and ring B are selected independently of each other and wherein:
ring A (including E and the unsaturation shown) is a 6-membered cycloalkenyl or heterocycloalkenyl ring;
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R6)-, -N(R6)-, -N(C(Y)F17)-, -N(C(Y)0R6)-, -N(C(Y)N(1=13)(R1 ))-, -C(0)-N(R11)-, _N(R11).c(0)_, _s(0)2_N(R11)_, (rs ) S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0 _N(R11)_c(y)-Nc-02._, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-, ring B is a substituted or unsubstituted aromatic ring;
R2, R3, R4, R5, Rs, R7, R8, Fis, R10, R11, R12, y, and p, X, R1, and the optional substituents on ring B are as defined in each of the embodiments described above in Formula (I).
In one embodiment, Formula (IV.a) has the general structure shown in Formula (IV.a.1):

X giS
' A
N

(IV.a.1).
In one embodiment, Formula (IV.a) has the general structure shown in Formula (IV.a.2):

)7-- X 4110 A E

(IV.a.2).

In one embodiment, Formula (IV.a) has the general structure shown in Formula (IV.a.3):

X itio N A E
I

(IV.a.3), wherein P is 0, 1, 2, or 3.
In one embodiment, Formula (IV.a) has the general structure shown in Formula (IV.a.4):

3 )p N A E

(IV.a.4), wherein P is 0, 1, 2, or 3.
In one embodiment, Formula (IV.a) has the general structure shown in Formula (IV.a.5):

X 0 õ
..-----tR3 A

(IV.a.5), wherein P is 0, 1, 2, or 3.
In one embodiment, Formula (IV.a) has the general structure shown in Formula (IV.a.6):

= ----4R3 N A
I

(IV.a.6), wherein P is 0, 1, 2, or 3.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), X is S.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), X is S(0).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), X is S(0)2.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), ring A is a cycloalkenyl ring and E is -C(R4)(115)-..
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -0-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -S-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -S(0)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -S(0)2-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(R4)(R5)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R6)-.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(C(Y)R7)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is--N(C(Y)0R8)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(C(Y)N(R8)(R16))-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(0)-N(R11)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R11)-C(0)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -S(0)2-N(R11)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R11)-S(0)2-=
In some embodiments, in each of Formulas (IV.a); (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(0)-0-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -0-C(0)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -0-N(R6)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R6)-0-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R6)-N(R12)-.

In some embodiments, in each of Formulas (IV.a), (1V.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N=N-.
In some embodiments, in each of Formulas (IV.a), (1V.a.1), (IV.a.2), (1V.a.3), (IV.a.4), (IV.a.5), and (1V.a.6), E is -C(137)=N-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(0)-C(R7)=N-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(0)-N=N-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -0-C(Y)-N(R11)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (1V.a.2), (1V.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R11)-C(Y)-0-.
In some ernbodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R11)-C(Y)-N(12112)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), =
(IV.a.4), (IV.a.5), and (IV.a.6), E is -C(Y)-N(R11)-0-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(Y)-N(R11)-N(R12)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -0-N(R11)-C(Y)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (1V.a.3), (1V.a.4), (IV.a.5), and (IV.a.6), E is -N(R12)-N(R11)-C(Y)-.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (1V.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=0).

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=S).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=N(R13)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=N(CN)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=N(OR14)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=N(I:115)(1:116)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Yds (=C(RI7)(R18)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), B is an unsubstituted aromatic ring.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), B is an unsubstituted benzo ring, and Formula (IV.a.) has the general structure:

110i R3) N A

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being . , independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, _NR23s02R24, -NR23C(0)0R20, -NR23C(0)R24, -S02NR26R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25m."'26, _NR23C(N-CN)NR25R26 and NR23C(0)NR26R26.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkjmyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, _NR23s02R24, -NR23C(0)0R20, -NR23C(0)R24, -S02NR26R26, _c(0¨)1124, C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, _NR23C(N-CN)NR25R26 and ¨
NR23C(0)NR26R26. In one such embodiment, ring B is benzo substituted with from 1 to 3 groups independently selected from halo.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R1 is unsubstituted aryl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), RI is unsubstituted phenyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (1V.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R1 is unsubstituted naphthyl. =
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (1V.a.4), (IV.a.5), and (IV.a.6), R1 is substituted aryl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (1V.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R1 is substituted phenyl.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R1 is substituted naphthyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), 111 is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R16, -S02R19, -0C(0) R24, -C(0)NR26R26, -NR23C(N-CN)N R26 R26 and -NR23c(o)NR25R26.
=
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (1V.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), 1=0 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, =
heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR251326, -NR23C(N-CN)NR251326 and -NR23C(0)NR251126.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.5), and (IV.a.6), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO2, -NR21R22, and haloalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R1 is selected from the group consisting of:

halal,- HO.......(.- NC.õlõ
02N.,õ1õ-S / halo ____ / ___ halo c\µ __ halo µS / halo , , haloalk-halo , ,and , .
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), RI is:
perfluoroalkylNls-S __ / __ halo =
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), RI is phenyl substituted with one to three fluoro groups.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), RI is phenyl substituted with two fluoro groups.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (1V.a.6), RI is phenyl substituted with one fluoro group.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R1 iÞ:
II F
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(Z)137.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(Z)NR9R10.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(Z)0R8.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -S02NR9R10.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is alkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is heteroalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is aryl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is heteroaryl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is cycloalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is cycloalkenyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is heterocycloalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is heterocycloalkenyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (.0).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=S).

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=N(R13)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=N(CN)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=N(01=114)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=N(R15)(R16)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=C(R17)(R18)).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(Z)I17, and Z is (=0).
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)H.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)alkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)CH3.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)F17, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR", -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR16, -S(0)1319, -S021116, -0C(0)1=124, -C(0)NR25R25, -NR23C(N-CN)NR25R25 and -NR23C(0)NR25R26.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -0R19, -NR21R22, and cycloalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)137, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH2, and cyclopropyl.
In some" embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with -OH.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)R7, wherein said R7 is unsubstituted heterocycloalkyl.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)R7, wherein said R7 is substituted heterocycloalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)R7, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, _c(cy)11 _ C(0)0R2 ,.-SR, -S(0)R19, -S02R16, -0C(0)R24, _ C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR29R26.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)R7, wherein said_137 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is selected from:
_ old , and H3/

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(0)NR9R19.

In some embodiments, in each of Formulas (IV.a), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)NH2-In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)NR9111 , wherein R9 and R1 can be the same or different, each being independently selected from alkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)NR9R10, wherein R9 is unsubstituted heterocycloalkyl and R1 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (1V.a.3), (IV.a.4), (IV.a.5), and (1V.a.6), R2 is ¨C(0)NR R10, wherein R9 is substituted heterocycloalkyl and R1 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is ¨C(0)NR9R10, wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R1 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is selected from the group consisting of:
alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)R7. ¨C(0)01:18, and -C(0)NR9R1 .
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is selected from the group consisting of 0 0 .Arv 3, 0 F2 o, .) .L.s.õ H ,y-k o , HO , s-rt .....r.,..c ..."YIN
ITI, 0 LO 0 0 1 .....0 , N. OH 7 OH , I 7 I
..,..s, siNf' RI 01..1"' .....N,_,...N....õ( 1.41-12, NH2 7 N H2 , NH2, 0 , ,..NH, .r, .rsr .,..'' ..... OjNi C)) ,,,,,,, .rjr.i, 0j) Nr 0 0 OJAT HN.,.....0 HN....,,-- NH s.

i I

H2N , H2N , H2N , cli.."'w0 o JCILO
H

'H2N
y "J. sJj'r .,,=-r'r av, J.
cp0 ,===0 c 0 0 c 0 0 - ( , . o C(NH 4,N7NH =Nu 828 , H2N
, ..rs ...,-ciso > .
o o cp-'-' H2N , H28 NH2 , N , N , NH , 0-7 , ..1....
sn.r.
1:::),.1 C)J.11 c,...õ) YN''NN l)(No 0 ,N-",õ--0 0 NH, 1----/, _________ H , and / .
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6),IR2 is In some embodiments, in each of Formulas (IV.a), (1V.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (1V.a.5), and (IV.a.6), R2 is .
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (1V.a.6), R2 is In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), H
(IV.a.4), (IV.a.5), and (IV.a.6), R2 is In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (1V.a.3), NHo (IV.a.4), (IV.a.5), and (IV.a.6), R2 is z In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is I .
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), o 122, N _______________________________ ( ¨
( I V . a . 4 ) , (IV.a.5), and (IV.a.6), R2 is .
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (1V.a.4), (IV.a.5), and (1V.a.6), p is 0 and R3 is not present.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 1.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 2.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.4), (IV.a.5), and (IV.a.6), p is 3.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 4.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is > 2 and at least two groups R3 are attached to the same ring atom.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 1 and R3 is independently selected from the group consistingof alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, -SR", -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In.some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 2, 3, or 4 and each 1:13 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R2 , -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR251326, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 2, 3, or 4 and at least two groups 133 are bound to the same ring carbon atom, wherein each R3, which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R26, -NR21e, -NR23s02R24, -NR23c(o)0R20, -NR23c(o)R24, -s02NR25R26, -c(o)R24, -c(0)0R20, -se, -s(o)e, -s02e, -oc(o)R24, -c(0)NR25R26, -NR23C(N-CN)NR261326 and -NR23C(0)NR261126.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein two R3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
In one embodiment, in Formula (IV.a), p is 1, 2, 3, or 4 and each R3 is independently selected from the group corisistin.g.of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R20, -NR21R22, _N Rnso2R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR25R26, -0(0)R24, -C(S)R24, -C(0)0R20, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26, -NR23C(0)NR25R26, and -NR23-C(NH)-N1126R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each sad heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OW 9, -0C(0)0 R29, -NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -502R19, -0C(0)R24, -C(0)NR291:126, -N R23C (N-CN)NR29 R26 and -NR23C(0)NR261326.
In one embodiment, in Formula (IV.a), p is 1 and FI3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -01316, -0C(0)01:126, -NR211322, -NR23S02R24, -NR23C(0)01326, -NR23C(0)R24, -SO2NR26R26, -C(0)1:124, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)1:124, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26.
In one embodiment, in Formula (IV.a), p is 2, 3, or 4 and any two R3 groups bound to the same ring A atom are taken together to form a ¨C(0)- group.
In one embodiment, in Formula (IV.a), p is 2, 3, or 4 and any two R3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the =group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatonns independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is alkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is heteroalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is alkenyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is heteroalkenyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is alkynyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is heteroalkynyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), =and (1V.a.6), R3 is aryl.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is heteroaryl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is cycloalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (1V.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is cycloalkenyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is heterocycloalkyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is heterocycloalkenyl.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is halogen.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is ¨CN.
In some ernbodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -NO2.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), =
(IV.a.4), (IV.a.5), and (IV.a.6), R3 is -0R19.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (1V.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -0C(0)0R29.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -NR21R22,.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -NR23S02R24.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -NR23C(0)0R29.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -NR23C(0)R24.

In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -S02NR25R26.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -C(0)R24.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -C(0)0R29.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -SR19.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -S(0)R19.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -S02R19,.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -0C(0)R24.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -C(0)NR25R26,.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.5), and (IV.a.6), R3 is -NR23C(N-CN)NR25R26.
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is ¨NR23C(0)NR25R26 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is selected from the group consisting of:
methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or 7.11.,- JUMP
branched), phenyl, N,N, NH2 H2N H2N \
OH, OH
..rvykr JUIN.
HN
L.-NH2 \ J HN
HN HN)--NH2 .%0H
, _ r HN\ N\0 OH ,and H2N .
In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), when E is ¨NR6-, R3 is absent.
=
In one embodiment, the compounds of the invention have a structure shown in Formula (IV.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:

.3) N_. A

(IV.b.) wherein X, R1, R2, R3, p, E, ring A, and ring B are selected independently of each other and wherein:
ring A (including E and the unsaturation shown) is a 6-membered cycloalkenyl or heterocycloalkenyl ring;
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R3)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)01:18)-, -N(O(Y)N(119)(1:113))-, -C(0)-N(1311)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(13")-, -N(R")-C(Y)-0-, -N(R1')-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-;
ring B is a substituted or unsubstituted heteroaromatic ring;
and p, X, R1, R2,133, R4, R6, R6, R7, R8, R9, R1 , R", R12, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I).
In one embodiment, Formula (IV.b) has the general structure shown in Formula (IV.b.1):
R1 =
lip R3) =
(IV.b.1).
In one embodiment, Formula (IV.b) has the general structure shown in Formula (IV.13.2):

R3) N -_ A
N
I

(1V.b.2).
In one embodiment, Formula (IV.b) has the general structure shown in Formula (IV.b.3):

\IT¨ X IMO
R 3 ) N A
I 7;

Ft 3 (IV.b.3), wherein P is 0, 1, 2, orl.
In one embodiment, Formula (IV.b) has the general structure shown in Formula (IV.b.4):
R x R2 =
- R3 ) N A

(IV.b.4), wherein P is 0, 1, 2, or 3.
In one embodiment, Formula (IV.b) has the general structure shown in Formula (IV.b.5):

R3 )P

(IV.b.5), wherein P is 0, 1, 2, or 3.
In one embodiment, Formula (IV.b) has the general structure shown in Formula (IV.b.6):

/ = R3) A
I ==

R' (IV.b.6), wherein P is 0, 1, 2, or 3.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.5), and (IV.b.6), X is S.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.5), and (IV.b.6), X is S(0).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.4), (IV.b.5), and (IV.b.6), X is S(0)2.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), ring A is a cycloalkenyl ring and E is -C(R4)(116)-..
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -0-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4),. (IV.b.5), and (IV.b.6), E is -S-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -S(0)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -S(0)2-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(R4)(116)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R6)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(C(Y)R7)-.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(C(Y)0R8)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(C(Y)N(R8)(R/0))-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(0)-N(R11)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R11)-C(0)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -S(0)2-N(R11)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R11)-S(0)2-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(0)-0-.
In some ernbodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -0-C(0)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -0-N(R8)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R8)-0-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R8)-N(R12)-.
In some embodiments, in each of Fomnulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N=N-.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (1V.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(1:17)=N-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(0)-C(117)=N-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(0)-N=N-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (1V.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -0-C(Y)-N(R11)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R11)-C(Y)-0-.
. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (1V.b.6), E is -N(R11)-C(Y)-N(R12)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(Y)-N(R11)-0-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), =
(IV.b.4), (IV.b.5), and (IV.b.6), E is -C(Y)-N(R11)-N(R12)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -0-N(R11)-C(Y)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R12)-N(R11)-C(Y)-.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (1V.b.6), Y is (=0).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (1V.b.5), and (IV.b.6), Y is (=S).

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=N(R13)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=N(CN)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=N(OR14)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=N(R15)(R16)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=C(R17)(R18)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted heteroaromatic ring.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group -consisting of N, 5, 0, S(0)., and 5(0)2-In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R15, -0C(0)0R26, -N R21 R22, _NR23s02R24, -NR23C(0)0R26, -NR23C(0)1:124, -SO2NR25R26, -C(0)R24, -C(0)0R26, -S(0)R19, -S02R19, -0C(0)R24, -C (0) N R25R26, -N R23C(N-C N)N R25R26 and ¨
N R23C(0)N eR26.
=

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is a 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0 R2 , -NR21R22, _NR23s02R24, -NR23C(0)0R29, -NR23C(0) R24, -S02 NIR25 -H, _26 C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)N R25 R26, _N
R23C(N1CN)NR29R26 and ¨
NR23C(0)NR29R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In some embodiments, in each of Formulas (IV.b), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is a 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl. haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)01:129, -NR23c(o) R24, -SO2NR25R25, -C(0)R24, -C(0)0R23, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and ¨NR23C(0)NR25R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and O.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.13.5), and (IV.b.6), B is a 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, =
=
which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0R19, -NRai R22, _c(o..-.)1124, C(0)0R29, -SR19, -S(0)R15, -S02R15, -0C(0)R24, and -C(0)NR25R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.3), =
=
(IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0 R29, -N R21 R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)N1325 R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and O.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is a 5-membered heteroaromatic ring having ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0R19, -NR21R22, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, and -C(0)NR25R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is a 5-membered heteroaromatic ring having S
as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0R19, -N R21 rs22, _ C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -5021119, -0C(0)R24, and -C(0)NR251126.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.13.6), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (1V.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is selected from the group consisting of , and In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), RI is unsubstituted aryl.
In some embodiments, in each of Formulas (IV.b), (1V.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (1V.b.5), and (IV.b.6), RI is unsubstituted phenyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (1V.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), RI is unsubstituted naphthyl.
In some embodiments, in each of Formulas (IV.b), (1V.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), RI is substituted aryl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (1V.b.4), (IV.b.5), and (IV.b.6), RI is substituted phenyl.
In some embodiments, in each of Formulas (IV.b), (1V.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), RI is substituted naphthyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), RI is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R29, -SR' 9, -S(0)R19, -S021:119, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), 111 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R23, -NR21R22, -NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -S02NR25R26, -C(0)1124, -C(0)0R23, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), iIV.b.5), and (IV.b.6), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO2, -NR21R22, and haloalkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R1 is selected from the group consisting of:
HO
_________________ halo (µ ___ halo \ / __ halo NS. __ halo .14.5j , Prij S-Pri SJjj alkyl _________________ halo ___________ halo ,and .rr-rs In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), ill is:

per9uoroalkyl.....4.-______________________ halo =
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), al is phenyl substituted with one to three fluoro groups.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R1 is phenyl substituted with two fluoro groups.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R1 is phenyl substituted with one fluoro group.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R1 is:= -. -In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(Z)F17.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(Z)NR8R10.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(Z)0R8.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -S02NR8R10.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is alkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is heteroalkyl.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is aryl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is heteroaryl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is cycloalkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is cycloalkenyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is heterocycloalkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is heterocycloalkenyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=0).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=S).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=N(R13)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=N(CN)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=N(0R14)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=N(R15)(R16)).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=C(R17)(R18)).

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(Z)R7, and Z is (=0).
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)H.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)alkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)CH3.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR29R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NIR25 R26, -NIR23C(N-CNI)NR29R26 and -NR23C(0)NR251:126.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)1R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -0R19, -NR21R22, and cycloalkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)117, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)F17, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH2, and cyclopropyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (11/.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)1R7, wherein said R7 is alkyl substituted with -OH.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is¨C(0)R7, wherein said R7 is unsubstituted heterocycloalkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)1R7, wherein said R7 is substituted heterocycloalkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)F17, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR29R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR291126, -NR23C(N-CN)NFI291326 and -NR23C(0)NR251326.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(0)R7, wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted nnorpholine, substituted pyrrolidine, and substituted azetidine.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is selected from:
¨c¨

H3C , and H3c/
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(0)NR9R19.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(0)NH2.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(0)NR9R19, wherein R9 and R19 can be the same or different, each being independently selected from alkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(0)NR9R19, wherein R9 is unsubstituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)NR9R19, wherein R9 is substituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is ¨C(0)NR9R19, wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R19 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.13.5), and (IV.b.6), R2 is selected from the group consisting of: alkyl, haloallwl, heteroalkyl, heterohaloalkyl, -C(0)R7. ¨C(0)0119, and -C(0)NR9R19.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is selected from the group consisting of ' , T 0 (:) .) __ 11 õ..- -..õ..OH YM::. zõ..11..õ...,0 isrv Cr.\ """" -^". .,,===== .,,, 0--\
lt,,jLO LO , 1, ---='-' , 1:),, , OH , OH , I

VIL", M U .... N.,........-.N.õ..k !In-12 NH2 NH2 NH2 , , 0. 2 ro HN,ro HNy,NH &__(-13 Ht,pc.p o NH
H

, g% 9Ao %AP

NH CNH NH ii2N(S) fC) H2-;Si H2N , NH2 NH , (:)..11 CI
N¨

)rNN(Th IYNC\NH , , q, and .
o In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), ;A-(IV.b.4), (IV.b.5), and (IV.b.6), 1:12 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is l'riLV
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is `z, In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), o (IV.b.4), (IV.b.5), and (IV.b.6), R2 is c.4 =
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), o NH
(IV.b.4), (IV.b.5), and (IV.b.6), R2 is In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is I .
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), o N .N¨

OV.b.4), (IV.b.5), and (IV.116), R2 is .
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 0 and R3 is not present.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3),.
(IV.b.4), (IV.b.5), and (IV.b.6), p is 1.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 2.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 3.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 4.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is > 2 and at least two groups R3 are attached to the same ring atom.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 1 and R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R20, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)1=124, -C(0)01120, -SR19, -S(0)R19, -S02R19, -0C(0)R14, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 2, 3, or 4 and at least two groups R3 are bound to the same 'ring carbon atom, wherein each R3, which may be the same or .
different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R29, -NRSO2R24, -NR23C(0)0R29, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR251:126.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein two R3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
In one embodiment, in Formula (IV.b), p is 1, 2, 3, or 4, and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)01129, -NR211122, -NR23S02R24, -NR23C(0)01129, -NR23C(0)R24, -S02NR25R26, -C(0)1124, -C(S)1124, -C(0)01=12 , -SR19, -S(0)R19, -SO2R19, -0C(0)1124, -C(0)NR25e, -NR23c(N-CN)N11251126, -NR23C(0)NR231126, and -NR23-C(NH)-NR26R29, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)01129, -NR21R22, -N1123S02R24, -NR23C(0)0R23, -N1123C(0)1124, -S02NR25R26, -C(0)1124, -C(0)0R23, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR251126, -NR23C(N-CN)NR25R26 and -NR23C(0)NR23R26.
In one embodiment, in Formula (IV.b), p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0F129, -NR211122, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR251126, -C(0)1124, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)N11125R26, -NR23C(N-CN)N1123R26 and -NR23C(0)N1125R26.

In one embodiment, in Formula (IV.b), p is 2, 3, or 4, and any two R3 groups bound to the same ring A atom are taken together to form a ¨C(0)- group.
In one embodiment, in Formula (IV.b), p is . 2 and any two R3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is alkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.5), and (IV.b.6), R3 is heteroalkyl.
-In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is alkenyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is heteroalkenyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is alkynyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is heteroalkynyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is aryl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is heteroaryl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is cycloalkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is cycloalkenyl.

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is heterocycloalkyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is heterocycloalkenyl.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is halogen.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is ¨CN.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -NO2.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV:b.6), R3 is -0R19.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -0C(0)0R20.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -NR21R22,.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -NR23S02R24.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -NR23C(0)0R20.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -NR23C(0)R24.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -S02NR25R26.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -C(0)R24.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -C(0)0R20 .

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -SR19.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -S(0)R19.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -SO2R19,.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -0C(0)R24.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -C(0)NR29R26,.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -NR23C(N-CN)NR23R36.
In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is ¨NR23C(0)NR23R26 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is selected from the group consisting of:
methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or VVV, N , NH H N HN
branched), phenyl, N , 2, 2 , 2 OH , srPr *NV, JNOV
OH, OH lyN H2 H N
HO, HN
0, o H N OH
H N )7---NH2 HN
\ 0 , OH , and H2N.
=

In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), when E is -NR6-, R3 is absent.
In one embodiment, the compounds of the invention have a structure shown in Formula (V.a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:

R3) N., A

= =
(V.a.) wherein X, R1, R2,1:13, p, E, ring A, and ring B are selected independently of each other and wherein:
ring A (including E and the unsaturation shown) is a 7- to 8-membered cycloalkenyl or heterocycloalkenyl ring;
E is selected from the group consisting of -0-, -S-, -S(0)2-, -C(R4)(É5)-, -N(116)-, -N(C(Y)R7)-, -N(C(Y)0R9)-, -N(C(Y)N(R9)(R19))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(1=16)-N(R12)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-;
ring B is a substituted or unsubstituted aromatic ring;
and p, X, R1, R2, R3, R4, Rs, R6, R7, Ra, R9, Rlo, R11, R12, Y, and the optional substituents on ring B are as defined in each of the embodiments described above in Formula (I).
In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.1):

X=

411) R3 )p N
N

(V.a.1).
In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.2):

R3 ) - A
-N
I

(V.a.2).
In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.3):

R_ X 41311 N
N
I µ; R 3 ) 2 ¨

(V.a.3), wherein P is 0, 1, 2, or 3.
In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.4):
R
\)--- X OM
R3) N A

(V.a.4), wherein P is 0, 1, 2, or 3.
In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.5):

X=

41) R3 ) -... P

(V.a.5), wherein P is 0, 1, 2, or 3.
In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.6): =
=

R3) N A
I :7_ 2 =-=

(V.a.6), wherein P is 0, 1, 2, or 3.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), X is S.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), X is S(0).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), X is S(0)2.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), ring A is a cycloalkenyl ring and E is -C(R4)(1716)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is selectedfrom the group consisting of -0-and -N(R6)-, wherein R6 is selected.from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -0-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), '(V.a.4), (V.a.5), arid (V.a.6); E is -S-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -S(0)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -S(0)2-=
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(R4)(R6)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R6)-.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(C(Y)117)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(C(Y)0R8)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(C(Y)N(R8)(R16))-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(0)-N(R11)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R11)-C(0)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -S(0)2-N(R11)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R11)-S(0)2-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E i-C(0)-O-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -0-C(0)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -0-N(R6)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R6)-0-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R6)-N(R12)-.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N=N-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(R7)=N-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(0)-C(R7)=N-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(0)-N=N-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -0-C(Y)-N(1311)-.
=
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(1111)-C(Y)-0-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R11)-C(Y)-N(R12)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), =
(V.a.4), (V.a.5), and (V.a.6), E is -C(Y)-N(R11)-0-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(Y)-N(R11)-N(R12)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -0-N(R11)-C(Y)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R12)-N(R11)-C(Y)-.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=0).

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=S).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=N(R13)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=N(CN)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=N(0R14)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=C(R17)(R18)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), B is an unsubstituted aromatic ring.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), B is an unsubstituted benzo ring, and Formula (IV.a.) has the general structure:
x R3) In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S021:124, -NR23C(0)0R29, -NR23C(0)R24, -S02NR251326, -C(0)R24, -C(0)0R29, -S(0)R19, -S021:119, -0C(0)R24, -C(0)NR291126, -NR23C(N-CN)NR25R26 and ¨
NR23C(0)NR291:126.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloallcyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR291126, -C(0)R24, -C(0)0R29, -S1119, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR291:126 and ¨
NR23C(0)NR25R26.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2) (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R1 is unsubstituted aryl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R1 is unsubstituted phenyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R1 is unsubstituted naphthyl.
In some ernbodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R1 is substituted aryl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R1 is substituted phenyl.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), IR1 is substituted naphthyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR261:126, -C(0)R24, C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR261126, _Nr-.11L23,==( N-CN)NR26R26 and -NR23C(0)NR26R26.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V..a.3), (V.a.4), (V.a.5), and (V.a.6), R1 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, _NR23s$02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR261326, -C(0)R24, -C(0)0R26, -SR16, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO2, -NR21R22, and haloalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Ill is selected from the group consisting of:

_______________________________________________________ halo .frjj , ,Prjj alkyl haloalkyl __________________ halo __________ halo ,and Pcjj In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), RI is:
______________________ halo =
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), RI is phenyl substituted with one to three fluoro groups.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), RI is phenyl substituted with two fluoro groups.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), RI is phenyl substituted with one fluoro group.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R1 is:
F = F
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(Z)R7.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(Z)NR8R10 .
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(Z)0R8.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -S02NR8R10.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is alkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is heteroalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is aryl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is heteroaryl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6),-R2. is cycloalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is cycloalkenyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is heterocycloalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is heterocycloalkenyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=0).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=S).

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=N(R13)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=N(CN)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=N(0R14)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=N(R15)(R16)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=C(R17)(R18)).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(Z)R7, and Z is (.0).
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is¨C(0)H.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)alkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)CH3.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R16, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR26R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R16, -S021319, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -0R19, -NR21R22, and cycloalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)F17, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.
In some embcidiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH2, and cyclopropyl.
in some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with -OH.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)R7, wherein said R7 is unsubstituted heterocycloalkyl.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)R7, wherein said R7 is substituted heterocycloalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)R7, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloallynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R15, -OC(o)0R20,_NR21R22, -NR23S02R24, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR25R-C(0)R24, -C(0)0R29, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R" and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a..5), and (V.a.6), R2 1s ¨C(0)137, wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is selected from:
I ---il , and H3c /N
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(0)NR51:116.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)NH2.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)NR9R19, wherein R9 and R19 can be the same or different, each being independently selected from alkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)NR9R19, wherein R9 is unsubstituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)NR9R19, wherein R9 is substituted heterocycloalkyl and R19 is selected from the group consisting of H and alkyl....
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is ¨C(0)NR9R19, wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R19 is selected from the group consisting of H and alkyl. =
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is selected from the group consisting of:
alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(0)R7. ¨C(0)0R8, and -C(0)NR9R19.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is selected from the group consisting of o ,Pf sr-r 5 , 0F3, d's CHF 2 F .õõ k , ..)Lv HO "t, is\
ogTh .rrrr .1 Ili, 0 0.1 yko (I ):1 , 0 OH , OH , v'T---, , 0 jµr o cd\
(10 i (371.1 NH2 , NH2 , ,...N.õ...õ...N.......k.
NH2, 0, ,NH , "4 , 0j) ojNi 0j)...1.,,--. ojslro FIN,r0 ElNy.NH eo HN,... 0 H , , H2N H2N H2N , , 8%..,' )0;10 ,c)0 , H ,H2N ,H2N , cliii 0 0 0 & 0. 0 OH 4NzNH 4NzNH H2CtN(67 O' N
2 , ,H
_pc .
,pr, ......-- =
..c) j.,, 0 Th ,6 ..,-, H2ì - , H2N NH , 1,1 O
C---) , N , NH , 0 , / )L _( \Ki 0(NC) \NH , 0 0..y.:1") R, and \ 7 r ¨.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Ft' õ
is `z, .

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), --)1--V
(V.a.4), (V.a.5), and (V.a.6), R2 is \ .
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), o (V.a.4), (V.a.5), and (V.a.6), R2 is '2, =
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), ,)c,0--...
(V.a.4), (V.a.5), and (V.a.6), R2 is In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is '4 .
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is I .
in some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), N¨CN¨

(V.a.4), (V.a.5), and (V.a.6), R2 is I .
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 0 and R3 is not present.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 1.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 2.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 3.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 4.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is > 2 and at least two groups R3 are attached to the same ring atom.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 1 and R3 is independently selected from the = = group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R23, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0F126, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR251:126, -NR23C(N-CN)NR25R26 and -NR23C(Q)NR25R26.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R25, -NR23C(0)R24, -S02NR251:126, .c(0)R24, -C(0)0R29, -SR19, -S(0)R19, -SO2R19, -0C(0)R24, -C(0)NR251:126, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein each R3, which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -N RC(0)R24, -SO2NR261326, -C(0)R24, -C(0)0R26, -SR13, -S(0)R13, -S02R19, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR261326.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein two R3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
In one embodiment, in Formula (V.a), p is 1, 2, 3, or 4, and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R13, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR26R26, -C(0)R24, -C(S)R24, -C(0)0R26, -S(0)R13, -S02R13, -0C(0)R24, -C(0)NR26R26, -NR23C(N-CN)NR26R26, -NR23C(0)NR261326, and -NR23-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R13, -0C(0)0R23, -NR21R22, -NR23S02R24, -NR23C(0)0R26, -NR23C(0)R24, -S02NR2611 26, _c(o)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, C(0)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26.
In one embodiment, in Formula (V.a), p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NR23S021:124, -NR23C(0)0R20, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R20, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR26R26 and -NR23C(0)NR26R26.
In one embodiment, in Formula (V.a), p is 2, 3, or 4, and any two R3 groups bound to the same ring A atom are taken together to form a ¨C(0)- group.
In one embodiment, in Formula (V.a), p is 2, 3, or 4,_and any two R3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, 0, S, S(0), and S(0)2.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is alkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is heteroalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is alkenyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is heteroalkenyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is alkynyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is heteroalkynyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is aryl.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is heteroaryl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is cycloalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is cycloalkenyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is heterocycloalkyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is heterocycloalkenyl.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is halogen.
=
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is ¨CN.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -NO2.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -0R19.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -0C(0)0R20.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -NR21R22,.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -NR23S02R24.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -NR23C(0)0R20.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -NR23C(0)R24.

In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -S02NR25R26.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -C(0)R24.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -C(0)0R29.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -SR19.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -S(0)R19.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -S02R19,.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is -0C(0)R24.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), 113 is -C(0)NR25R26,.
n some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), = -(V.a.4), (V.a.5), and (V.a.6), R3 is -NR23C(N-CN)NR251126.
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is ¨NR23C(0)N R251126 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R3 is selected from the group consisting of:
methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or '111, .141 rrrEr , branched), phenyl, N, NH2, H 2N , H 2N OH, .rrrr JVW
NOW
HN
T: r ¨OH = H2 H
HN HN)r_NH2 fl HN, \, OH , and H2 N .
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), when E is ¨NR6-, R3 is absent.

In one embodiment. the compounds of the invention have a structure shown in Formula (V.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds:

R3) A

(V.b.) wherein X, R1, R2,1:13, p, E, ring A, and ring B are selected independently of each . other and wherein:
ring A (including E and the unsaturation shown) is a 7-8-membered cycloalkenyl or heterocycloalkenyl ring;
E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(1=19)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)01:19)-, -N(C(Y)N(R9)(R19))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(1312)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-;
ring B is a substituted or unsubstituted heteroaromatic ring;
and p, X, R1, R2, R3, R4, R9, R6, R7, R9, R9, R19, R11, R12, Y, and the optional substituents on ring B are as defined above in Formula (l).
In one embodiment, in Formula (V.b.), X is S.
In one embodiment, in Formula (V.b.), X is S(0).
In one embodiment, in Formula (V.b.), X is S(0)2.

In one embodiment, in Formula (V.b.), ring A is a cycloalkenyl ring.
In one embodiment, in Formula (V.b.), ring A is a heterocycloalkenyl ring.
In one embodiment, in Formula (V.b.), E is -C(R4)(1:15)-.
In one embodiment, in Formula (V.b.), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)01:18)-, -N(C(Y)N(R9)(e))-, -C(0)-N(R11)-, -N(R11)-C(0)-, -S(0)2-N(R11)-, -N(R11)-S(0)2-, -C(0)-0-, -0-C(0)-, -0-N(R6)-, -N(R6)-0-, -N(R6)-N(1:112)-, -N=N-, -C(R7)=N-, -C(0)-C(R7)=N-, -C(0)-N=N-, -0-C(Y)-N(R11)-, -N(R11)-C(Y)-0-, -N(R11)-C(Y)-N(F112)-, -C(Y)-N(R1')-0-, -C(Y)-N(R11)-N(R12)-, -0-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-.
In one embodiment,. in Formula (V.b.), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-.
In one embodiment, in Formula (V.b.), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In one embodiment, in Formula (V.b.), E is selected from the group consisting of -0- and -N(R6)-, wherein R6 is selected from the group consisting of H, alkyl, -C(0)R24, and -C(S)R24.
In one embodiment, in Formula (V.b.), E is -0, In one embodiment, in Formula (V.b.), E is -S-.
In one embodiment, in Formula (V.b.), E is -S(0)-.
In one embodiment, in Formula (V.b.), E is -S(0)2-.
In one embodiment, in Formula (V.b.), E is -C(R4)(R5)-.
In one embodiment, in Formula (V.b.), E is -N(R6)-.
In one embodiment, in Formula (V.b.), E is -N(C(Y)117)-.

In one embodiment, in Formula (V.b.), E is -N(C(Y)0R8)-.
In one embodiment, in Formula (V.b.), E is -N(C(Y)N(R6)(1116))-.
In one embodiment, in Formula (V.b.), E is -C(0)-N(R11)-.
In one embodiment, in Formula (V.b.), E is -N(R11)-C(0)-.
In one embodiment, in Formula (V.b.), E is -S(0)2-N(R11)-.
In one embodiment, in Formula (V.b.), E is -N(R11)-S(0)2-.
In one embodiment, in Formula (V.b.), E is -C(0)-0-.
In one embodiment, in Formula (V.b.), E is -0-C(0)-.
In one embodiment, in Formula (V.b.), E is -0-N(R6)-.' In one embodiment, in Formula (V.b.), E is -N(R6)-0-.
In one embodiment, in Formula (V.b.), E is -N(R6)-N(R12)-.
In one embodiment, in Formula (V.b.), E is -N=N-.
In one embodiment, in Fcirrnula (V.b.), E is -C(R7)=N-:
In one embodiment, in Formula (V.b.), E is -C(0)-C(117)=N-.
In one embodiment, in Formula (V.b.), E is -C(0)-N=N-.
In one embodiment, in Formula (V.b.), E is -0-C(Y)-N(R11)-.
In one embodiment, in Formula (V.b.), E is -N(R11)-C(Y)-0-.
In one embodiment, in Formula (V.b.), E is -N(R11)-C(Y)-N(R12)-.
In one embodiment, in Formula (V.b.), E is -C(Y)-N(R11)-0-.
In one embodiment, in Formula (V.b.), E is -C(Y)-N(1311)-N(R12)-.
In one embodiment, in Formula (V.b.), E is -0-N(R11)-C(Y)-.

In one embodiment, in Formula (V.b.), E is -N(1112)-N(R11)-C(Y)-.
In one embodiment, in Formula (V.b.), Y is (.0).
In one embodiment, in Formula (V.b.), Y is (=S).
In one embodiment, in Formula (V.b.), Y is (=N(R13)).
In one embodiment, in Formula (V.b.), Y is (=N(CN)).
In one embodiment, in Formula (V.b.), Y is (=N(OR14)).
In one embodiment, in Formula (V.b.), Y is (=N(R16)(R16)).
In one embodiment, in Formula (V.b.), Y is (=C(R17)(R16)).
In one embodiment, in Formula (V.b.), B is an unsubstituted heteroaromatic ring.
In one embodiment, in Formula (V.b.), B is an unsubstituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2.
In one embodiment, in Formula (V.b.), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OG(0)01=1213, -NR21R22, -NR23S021124, -NR23C(0)01126, -NR23C(0)R24, -SO2N1126R26, -C(0)R24, -C(0)0R26, -SR13, -S(0)R13, -SO2R13, -0C(0)1:124, -C(0)NR26R26, -NR23C(N-CN)NeR26 and ¨NR23C(0)NR26R26.
In one embodiment, in Formula (V.b.), B is a 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(0), and S(0)2, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR251:126, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (V.b.), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In one embodiment, in Formula (V.b.), B is a 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -s02NeR26, -c(0)0R20, -saw, -spos, -s02R19, -oc(o)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (V.b.), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and O.

In one embodiment, in Formula (V.b.), B is a 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0R19, -NR21 R22, .c(0).-.24, C(0)0R20, -SR13, -S(0)R13, -S02R13, -0C(0)R24, and -C(0)NR25R26.
In one embodiment, in Formula (V.b.), B is an unsubstituted 5-membered heteroaromatic ring haying from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and O.
In one embodiment, in Formula (V.b.), 13 is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R29, -NR21R22, _NR23s02.-.24, _ 23 NR¨C(0)0R2 , -NR23C(0)R24, _SO2NR25R26, -C(0)R24, -C(0)0R29, -S1319, -S(0)1119, -SO2R13, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and ¨NR23C(0)NR25R26.
In one embodiment, in Formula (V.b.), 13 is an unsubstituted 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and O.

In one embodiment, in Formula (V.b.), B is a 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0R19, -NR21R22, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, and -C(0)NR25R26.
In one embodiment, in Formula (V.b.), B is a 5-membered heteroaromatic ring having S as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, -0R19, -NR21 2R 2, _c(0)-245 _ C(0)0R2 , -SR19, = -S(0)R19, -SO2R19, -0C(0)R24, and -C(0)NR25R26.
In one embodiment, in Formula (V.b.), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom.
. In one embodiment, in Formula (V.b.), B is selected from the group consisting of õcs ,and In one embodiment, in Formula (V.b.), R1 is unsubstituted aryl.
In one embodiment, in Formula (V.b.), R1 is unsubstituted phenyl.
In one embodiment, in Formula (V.b.), R1 is unsubstituted naphthyl.
In one embodiment, in Formula (V.b.), R1 is substituted aryl.
In one embodiment, in Formula (V.b.), R1 is substituted phenyl.
In one embodiment, in Formula (V.b.), R1 is substituted naphthyl.

In one embodiment, in Formula (V.b.), R1 is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R20, -NR21R22, -NI:123502e, -NR23C(0)01R23, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)01:120, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (V.b.), R1 is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from tha grOUp consisting halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyt, azido, -0R19, -0C(0)0R2 , -NR21R22, -NR23S02R24, -NR23C(0)01:126, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R26, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R25 and -NR23C(0)NR25R26.
In one embodiment, in Formula (V.b.), R1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, and haloalkyl.
In one embodiment, in Formula (V.b.), R1 is selected from the group consisting of:

HO....1õ¨ NC......../õ¨ 02N.¨

halo k. / ____________________ halo S / ___ halo / __ halo , alkyl¨ haloalkyl....4õ¨

/ ________________ halo( / ___ halo ,and .
In one embodiment, in Formula (V.b.), R1 is:
perfluoroalkyl..õ.../,¨

.S /..p., _____________ halo.
In one embodiment, in Formula (V.b.), R1 is phenyl substituted with one to three fluoro groups.
In one embodiment, in Formula (V.b.), R1 is phenyl substituted with two fluoro groups.
In one embodiment, in Formula (V.b.), R1 is phenyl substituted with one fluoro group. = = . =
In one embodiment, in Formula (V.b.), R1 is:
F . F
."
In one embodiment, in Formula (V.b.), R2 is -C(Z)R7.
In one embodiment, in Formula (V.b.), R2 is -C(Z)NR8R10.
In one embodiment, in Formula (V.b.), R2 is -C(Z)0R8.
In one embodiment, in Formula (V.b.), R2 is -S02NR8R10.
In one embodiment, in Formula (V.b.), R2 is alkyl.

In one embodiment, in Formula (V.b.), R2 is heteroalkyl.
In one embodiment, in Formula (V.b.), R2 is aryl.
In one embodiment, in Formula (V.b.), R2 is heteroaryl.
In one embodiment, in Formula (V.b.), R2 is cycloalkyl.
In one embodiment, in Formula (V.b.), R2 is cycloalkenyl.
In one embodiment, in Formula (V.b.), R2 is heterocycloalkyl.
In one embodiment, in Formula (V.b.), R2 is heterocycloalkenyl.
In one embodiment, in Formula (V.b.), Z is (=0).
In one embodiment, in Formula (V.b.), Z is (=S).
In one embodiment, in Formula (V.b.), Z is (=N(R13)).
In one embodiment, in Formula (V.b.), Z is (=N(CN)).
In one embodiment, in Formula (V.b.), Z is (=N(0R14)).
In one embodiment, in Formula (V.b.), Z is (=N(R15)(R16)).
In one embodiment, in Formula (V.b.), Z is (=C(R17)(R19)).
In one embodiment, in Formula (V.b.), R2 is -C(Z)F17, and Z is (=0).
In one embodiment, in Formula (V.b.), R2 is ¨C(0)H.
In one embodiment, in Formula (V.b.), R2 is ¨C(0)alkyl.
In one embodiment, in Formula (V.b.), R2 is ¨C(0)CH3.
In one embodiment, in Formula (V.b.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, -NR23S02R24, -NR23C(0)0R29, -NR23C(0)R24, -SO2NR25R26, -C(0)R24, -C(0)0R29, -SR 19, -S(0)R19, -S02R16, -0C(0)R24, -C(0)NR26 R26, -NI R23C(N-CN) N R26 R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (V.b.), R2 is ¨C(0)117, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -0R19, and cycloalkyl.
In one embodiment, in Formula (V.b.), R2 is¨C(0)R7, wherein said R7 is alkyl, wherein said alkyl is substituted with alkyl and -OH.
In one embodiment, in Formula (V.b.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH2, and cyclopropyl. -In one embodiment, in Formula (V.b.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH2, and cyclopropyl.
In one embodiment, in Formula (V.b.), R2 is ¨C(0)R7, wherein said R7 is alkyl substituted with -OH.
In one embodiment, in Formula (V.b.), R2 is ¨C(0)R7, wherein said R7 is unsubstituted heterocycloalkyl.

In one embodiment, in Formula (V.b.), R2 is -C(0)R7, wherein said R7 is substituted heterocycloalkyl.
In one embodiment, in Formula (V.b.), R2 is -C(0)R7, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkryl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R2 , -N R21 R22, -NR23S02R24, -NR23C(0)0R2 , -NR23C(0)R24, -S02NR25R26, _c(o)R24, -C(0)0R20, -SR13, -S(0)R16, -S02R16, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)N R25R26.
In one embodiment, in Formula (V.b.), R2 is -C(0)1R7, wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine.
In one embodiment, in Formula (V.b.), R2 is selected from:
II
I -¨c¨

/.
H3C , and H3c =
In one embodiment, in Formula (V.b.), R2 is -C(0)NR9R1 .
In one embodiment, in Formula (V.b.), R2 is -C(0)NH2.
In one embodiment, in Formula (V.b.), R2 is -C(0)NR9R1 , wherein R9 and 131 can be the same or different, each being independently selected from alkyl.
In one embodiment, in Formula (V.b.), R2 is -C(0)NR9R10, wherein R9 is unsubstituted heterocycloalkyl and R1 is selected from the group consisting of H
and alkyl.

In one embodiment, in Formula (V.b.), R2 is ¨C(0)NR9R10, wherein R9 is substituted heterocycloalkyl and R1 is selected from the group consisting of H
and alkyl.
In one embodiment, in Formula (V.b.), R2 is ¨C(0)NR9R10, wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R1 is selected from the group consisting of H and alkyl.

-4)1-, In one embodiment, in Formula (V.b.), R2 is .1, C. 3.

\---1*
In one embodiment, in Formula (V.b.), F.,r- is .

-.)C7 In one embodiment, in Formula (V.b.), R2 is\ .

, In one embodiment, in Formula (V.b.), R2 is ., In one embodiment, in Formula (V.b.), R` is c2, .

In one embodiment, in Formula (V.b.), R2 is z 2=

\ N
In one embodiment, in Formula (V.b.), R2 is l .

}--- \
( ,N¨

In one embodiment, in Formula (V.b.), R2 is ___ I i .
, In one embodiment, in Formula (V.b.), p is 0 and R3 is not present.
In one embodiment, in Formula (V.b.), p is 1.
In one embodiment, in Formula (V.b.), p is 2.
In one embodiment, in Formula (V.b.), p is 3.
In one embodiment, in Formula (V.b.), p is 4.
In one embodiment, in Formula (V.b.), p is > 2 and at least two groups R3 are attached to the same ring atom.
In one embodiment, in Formula (V.b.), p is 1 and R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2, ; -bR19, -0C(0)01325, -NR211:122, -NR23S02R24, -NR23C(0)01:120, -N11:123C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0F120, -SR19, -S(0)R19, -S02R19, -0C(0)1:124, -C(0)NR25R26, -N1123C(N-CN)N1325R26 and -NR23C(0)N1325R26.
In one embodiment, in Formula (V.b.), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)0R25, -NR21F122, -NR23S021:124, -NR23C(0)0R25, -NR23C(0)R24, -S02NR25R26, -C(0)1=124, -C(0)01=12 , -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR251:126 and -NR23C(0)NR25R26.
In one embodiment, in Formula (V.b.), p is 2, 3, or 4 and at least two groups are bound to the same ring carbon atom, wherein each R3, which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2õ -0R19, -0C(0)01:125, _NR21R22, -NR23S02R24, -NR23C(0)0R25, -NR23C(0)R24, -S02NR25R26, _c(0-24, _ C(0)01=12 , -SR19, -S(0)R19, -S02R19, -0C(0)R24, -c(o)NeR26, -NR23C(N-CN)NR251:126 and -NR23C(0)NR251326.

In one embodiment, in Formula (V.b.), p is 2, 3, or 4 and at least two groups are bound to the same ring carbon atom, wherein two R3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
In one embodiment, in Formula (V.b), p is > 0 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -0R19, -0C(0)0R2 _NR21-22, _ NR23S02R24, -NR23C(0)0R26, -NR23c (o)R24, -so2NR25R26, _c (0- -)H, _24 C(S)R24, -C(0)0R29, -SR19, -S(0)R19, -S02R19, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26, -NR23C(0)NR25R26, and -NR23-C(NH)-NR26R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, .
heterocycloalkyl, heterocycloalkenyl, azido, -0R19, -0C(0)0R26, -NR21R22, _NR23s02-24, NR23C(0)0R26, -NR23C(0)R24, -S02NR25R26, -C(0)R24, -C(0)0R26, -SR", -S(0):115, -S02R13, -0C(0)R24, -C(0)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(0)NR25R26.
In one embodiment, in Formula (V.b), p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haioaikyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, DEMANDES OU BREVETS VOLUMINEUX
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Claims (31)

433
1. A compound having the general structure shown in Formula (I), or a pharmaceutically acceptable salt, solvate, or ester thereof:
wherein X, R1, R2, R3, p, E, ring A, and ring B are selected independently of each other and wherein:
p is 0, 1, 2, 3, or 4;
X is selected from the group consisting of S, S(O), and S(O)2;
ring A includes E and the unsaturation shown in formula (I), forming a 4-8 membered ring;
E is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, -C(R4)(R5)-, -N(R6)-, -N(C(Y)R7)-, -N(C(Y)OR8)-, -N(C(Y)N(R9)(R10))-, -C(O)-N(R11)-, -N(R11)-C(O)-, -S(O)2-N(R11)-, -N(R11)-S(O)2-, -C(O)-O-, -O-C(O)-, -O-N(R6)-, -N(R6)-O-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(O)-C(R7)=N-, -C(O)-N=N-, -O-C(Y)-N(R11)-, -N(R11)-C(Y)-O-, -N(R11)-C(Y)-N(R12)-, -C(Y)-N(R11)-O-, -C(Y)-N(R11)-N(R12)-, -O-N(R11)-C(Y)-, and -N(R12)-N(R11)-C(Y)-, wherein each Y is independently selected from the group consisting of (=O), (=S), (=N(R13)), (=N(CN)), (=N(OR14)), (=N(R15)(R16)), and (=C(R17)(R18));

ring B is an aromatic or heteroaromatic ring, or a partially unsaturated alicyclic ring, or a partially unsatureted heterocyclic ring, wherein said ring is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being Independently selected front the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and ¨NR23C(O)NR25R26;
R1 is phenyl optionally substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of halogen, -OH, -CN, -NO2, haloalkyl, and ¨NR21R22;
R2 is selected from the group consisting of -C(Z)R7, -C(Z)NR9R10 and ¨C(Z)OR6, wherein each Z is independently selected from the group consisting of (=O), (=S), (=N(R13)), (=N(CN)), (=N(OR14)), (=N(R15)(R16)), and (=C(R17)(R18)) ;

each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23O(O)R24, -SO2NR25R26, -C(O)R24, -C(S)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26, -NR23C(O)NR25R26, and -NR23-C(NH)-N(R26)2, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR62R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26, or, alternatively, when p is 2, 3, or4, any two R3 groups bound to the same ring carbon atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, or a spiroheterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(O)-, -S(O)2-, and -O-, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(O)-, -S(O)2, and -O-, or, alternatively, R2 and R3, together with the atom to which they are attached, are taken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three ring heteroatoms Independently selected from the group consisting of -NH-, -NR6-, -S-, -S(O)-, -S(O)2-, and -O-, or a heterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(O)-, -S(O)2-, and -O-;
each R4 (when not joined with R6) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2, -OR19, -OC(O)OR26, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR16, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26, wherein each said alkyl, each saki heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR22SO2R24, -NR23C,(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
each R5 (when not joined with R4) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO2, , -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R14, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
or, alternatively, R4 and R5, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22,-NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
each R6 is Independently selected from the group consisting of H, alkyl, -C(O)R24, -C(O)OR20, -C(S)R24, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being Independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(S)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
each R7 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally Independently substituted with one or more substituents, the same or different. each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R9, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
each R8 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituentsr the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23(O)R24, -SO2NR25R26, -C(O)R4, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
each R9 (when not joined with R10 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R23, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR4C(O)NR25R26;
each R19 (when not joined with R9) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl aryl.
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
or, alternatively, R9 and R10, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstltuted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2N25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;

each R11 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkylyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each sald heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR10, -S(O)R19, -SO z R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
each R12 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each saki cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally Independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -S02R18, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;

each R13 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR10, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
each R14 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;

each R15 (when not Joined with R16) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl Is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azIdo, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -S(O)R19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR26R26;
each R16 (when not joined with R16) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, hetaroalkenyl, alkynyl, heteroalkynyl, aryl. heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO3NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26:

or, alternatively, R16 and R16, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R24, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
each R17 (when not joined with R14) is independently selected from the group consisting of H. alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -CN, -OC(O)OR20, -OR19. -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR26, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR26R26, -NR23C(N-CN)NR26R26 and -NR23C(O)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstltuted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azIdo, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;

each R18 (when not joined with R17) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -CN, -OC(O)OR20, -OR19, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl Is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being Independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19,-S(O)R19, -SO2R18, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26;
or, alternatively, R17 and R18, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S.
or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S.
wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26. -NR23C(N-CN)NR25R26 and ¨NR23C(O)NR23R26, each R19 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, and halocycloalkyl, each R20 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, and halocycloalkyl, each R21 (when not joined with R22) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, and halocycloalkyl, each R22 (when not Joined with R21) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, and halocycloalkyl, or, alternatively, R21 and R22, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S;
each R23 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, and halocycloalkyl, each R24 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl. aryl, heteroaryl, cycloalkyl, and halocycloalkyl;
each R25 (when not Joined with R26) Is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, and halocycloalkyl, and each R26 (when not Joined with R25) is independently selected from the group consisting of H. alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, hetecoaryl, cycloalkyl, and halocycloalkyl, or, alternatively, R26 end R26, together with the N atom to wtilch they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, O, and S
2. A compound of claim 1, wherein ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -O-and -N(R6)-.
3. A compound of claim 2, wherein R6 is selected from the group consisting of H, alkyl, -C(O)R24, -C(O)OR20, and -C(S)R24.
4. A compound of claim 3, wherein ring A is a 5-membered heterocycloalkylene ring.
5. A compound of claim 3, wherein ring A is a 6-membered heterocycloalkylene ring.
6. A compound of claim 1, wherein ring B is an unsubstituted aromatic ring or an aromatic ring which Is substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26.
7. A compound of claim 1, wherein ring B is an unsubstituted benzo ring or a benzo ring which is substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24.
-SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26.
8. A compound of claim 1, wherein R' is phenyl optionally substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of halogen, -OH, -CN, -NO2, haloalkyl, and ¨NR21-R22.
9. A compound of claim 1, wherein R1 is phenyl substituted with one to four substituents, the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,¨NO2, -NR21R22, and haloalkyl.
10. A compound of claim 1, wherein R1 Is selected from the group consisting of:
11. A compound of claim 1, wherein R1 is a moiety selected from the group consisting of:
12. A compound of claim 1, wherein R1 is:
13 A compound of claim 1, wherein R2 is selected from the group consisting of -C(O)R2, -C(O)NR9R10, and -C(O)OR8.
14. A compound of claim 1, wherein p is 0 and R3 is not present.
15. A compound of claim 1, wherein p is 1, 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -OR19, -OC(O)OR20, -NR21R22, -C(O)R24, -C(S)R24, -C(O)OR2, and -C(O)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, the same or different each substltuent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23O(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR23R25 and -NR23C(O)NR25R26.
16. A compound of claim 1, wherein p is 2, 3, or 4, and any two R3 groups bound to the same ring A atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, a spiroheterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(O)-, -S(O)2-, and -O-, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR6-, -S-, -S(O)-, -S(O)2-, and -O-.
17. A compound of claim 1, wherein R2 and R3 are taken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of ¨NH-, -NR6-, -S-, -S(O)-, -S(O)2-, and ¨O-, or a heterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of ¨NH-, -NR5-, -S-, -S(O)-, -S(O)2-, and ¨O-.
18. A compound of Claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof, having the general structure shown in Formula (IV):
E is selected from the group consisting of -C(R4)(R6)-, -O-, -S-, -S(O)-, -S(O)2-, and -N(R6)-;
ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms is the same or different, each ring heteroatom being independently selected from the group consisting of N, S, O, S(O), and S(O)2, said substituents on said aromatic ring or said heteroaromatic ring (when present) being independently selected from the group consisting of halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR26, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, -NR23C(N-CN)NR25R26 and ¨
NR23C(O)NR25R26;

R1 is phenyl optionally substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of halogen, -OH, -ON, -NO2, haloalkyl, and ¨NR21R22, R2 is selected from the group consisting of -C(O)R7, -C(O)NR9R13, and -C(O)OR6;
p is 0, 1, or 2; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO2, -OR19, -OC(O)0R20, -NR21R22,-C(O)R24 -C(S)R24, -C(O)OR20, and -C(O)NR25R26, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being Independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19. -OC(O)OR4, -NR21R22, -NR23SO2R24, -NR23C(O)OR29, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR10, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26.
-NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26.
19. A compound of Claim 18, wherein;
E is selected from the group consisting of -O- and -N(R6)-;
ring B is an unsubstltuted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, iSothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazlnyl, pyrimIdinyl, pyrazinyl, and triazinyl;

R1 is phenyl substituted with one to four substituents, the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CR¨NO2, -NR21R22, and haloalkyl;
R2 is selected from the group consisting of -C(O)R7, -C(O)NR9R10, and -C(O)OR8;
p is 0 or 1; and each R2 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl,.and heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR21R22, -NR23SO2R24, -NR23C(O)OR20, -NR23C(O)R24, -SO2NR25R26, -C(O)R24, -C(O)OR20, -SR19, -S(O)R19, -SO2R19, -OC(O)R24, -C(O)NR25R26, .-NR23C(N-CN)NR25R26 and -NR23C(O)NR25R26.
20. A compound of claim 19, wherein R1 is:
R6 is selected from the group consisting of H, alkyl, -C(O)R24, -C(O)OR20, and -C(S)R24.
21. A compound, or a pharmaceutically acceptable salt, solvate, or ester thereof, selected from the group consisting of:

22. A pharmaceutical composition comprising at least one compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or ester thereof , and at least one pharmaceutically acceptable carrier.
23. A pharmaceutical composition of claim 22, further comprising at least one additional therapeutically active agent
24. A pharmaceutical composition of claim 23, wherein said at least one additional therapeutically active agent is selected from the group consisting of:
estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors/stabilizing agents, topoisomerase inhibitors, antisense RNA oligonucleotides, antisense DNA
oligonucleotides, antimetabolites, antibodies coupled to cyctottlxic agents, r6dioisotypes, HMG-CoA reductase inhibitors, prenyltransferase inhibitors, famesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, MDR inhibitors, hypoxia activatable agents, proteasome inhibitors, ubiqüitin inhibitors, HOW inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors and interferon.
25. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt, solvate, or ester thereof, for use in treating a disease associated with or caused by aberrant cellular proliferation.
26. The compound of claim 25 for use in treating a disease selected from the group consisting of cancer, hyperplasia, cardiac hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, immune disorders, inflammation, tumor angiogenesis, and cellular proliferation induced by a medical procedure.
27. The compound of claim 25 for use in treating a disease selected from the group consisting of solid tumor cancer and hematological cancer.
28. The compound of claim 25 for use in treating a disease selected from the group consisting of skin cancer, breast cancer, brain cancer, colon cancer, gall bladder cancer, thyroid cancer, cervics cancer, testicular cancer, and blood cancer.
29. The compound of claim 25 for use in treating a disease selected from the group consisting of cardiac cancer, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, hematologic cancer, skin cancer, cancer of the adrenal gland, xenoderoma pigmentosum, keratoctanthoma, and thyroid follicular cancer.
30, The compound of claim 25 for use in treating a disease selected from the group consisting of adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia, squamous cell earoiribma, tranaltional cell carcinoma, adenocarcirtoma, prostate cancer, testicular cancer, hepatoma (hepatocallular carcinoma), chblangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrbsarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors.

osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, gerrninoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, meningioma, glioma, sarcoma;
endometrial carcinoma, cervical carcinoma, pre-tumor cervical dysplasia, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube carcinoma;
acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplaStic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkett's lymphoma, promyelocytic leukemia;
malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, liporna, angioma, dermatofibroma, keloids, psoriasis, and neuroblastoma.
31. The compound of any one of claims 1-21 and radiation for use in treating a disease of claim 30.
.82. The compound of any one of claims 1-21 for use in treating a disease of claim 25, the treatment further comprising at least one additional therapeutically active agent selected froth the group consisting of:
estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors/stabilizing agents, topoisomerase inhibitors, antitense RNA, antisense DNA
oligonudeotides, antimetabolites, antibodies coupled to cyctotoxic agents, radioisotypes, HMG-CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, MDR

inhibitors, hypoxia activatable agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E
inhibitor and interferon,
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